Kaletra oral solution

  • Name:

    Kaletra oral solution

  • Company:
    info
  • Active Ingredients:

    Lopinavir, Ritonavir

  • Legal Category:

    Product subject to restricted prescription (C)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 05/11/19

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Summary of Product Characteristics last updated on medicines.ie: 5/11/2019

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AbbVie Limited

AbbVie Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Chirocaine 1.25mg/ml solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 2.5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 7.5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Duodopa intestinal gel Active Ingredients Carbidopa Monohydrate, Levodopa
Medicine Name Forane 99.9% w/w, inhalation vapour liquid Active Ingredients Isoflurane
Medicine Name Humira 20 mg solution for injection in pre-filled syringe Active Ingredients adalimumab
Medicine Name Humira 40 mg solution for injection in pre-filled syringe Active Ingredients adalimumab
Medicine Name Humira 40mg solution for injection in pre-filled pen Active Ingredients adalimumab
Medicine Name Humira 80 mg solution for injection in pre-filled pen Active Ingredients adalimumab
Medicine Name Kaletra 200 mg/50 mg film-coated tablets Active Ingredients Lopinavir, Ritonavir
Medicine Name Kaletra oral solution Active Ingredients Lopinavir, Ritonavir
Medicine Name Maviret 100 mg-40 mg film-coated tablets Active Ingredients Glecaprevir, Pibrentasvir
Medicine Name Norvir 100 mg powder for oral suspension Active Ingredients Ritonavir
Medicine Name Norvir 100mg Film-coated Tablets Active Ingredients Ritonavir
Medicine Name RINVOQ 15 mg prolonged-release tablets Active Ingredients Upadacitinib
Medicine Name Sevorane Active Ingredients Sevoflurane
Medicine Name Skyrizi 75 mg solution for injection in pre-filled syringe Active Ingredients Risankizumab
Medicine Name Synagis Solution for Injection Active Ingredients Palivizumab
Medicine Name Venclyxto 10mg, 50mg and 100mg Film-coated Tablets Active Ingredients Venetoclax
Medicine Name Zemplar 5 microgram/ml Solution for Injection Active Ingredients Paricalcitol
Medicine Name Zemplar capsules, soft Active Ingredients Paricalcitol
1 - 0 of 22 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 5 November 2019 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to restricted prescription (C)

Updated on 5 November 2019 PIL

Reasons for updating

  • Change to section 4 - possible side effects

Updated on 27 September 2019 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to restricted prescription (C)

Updated on 27 September 2019 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink

Updated on 11 July 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 11 July 2019 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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)

     
  • 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

     

Updated on 9 May 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink

Updated on 8 May 2019 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

 

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

Updated on 12 November 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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).

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

Updated on 1 October 2018 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 26 September 2018 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 26 September 2018 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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

Updated on 15 August 2018 SmPC

Reasons for updating

  • File format updated to PDF

Legal category: Product subject to restricted prescription (C)

Updated on 3 July 2018

Updated on 6 June 2018 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to restricted prescription (C)

Updated on 6 June 2018 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder

Updated on 20 October 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to restricted prescription (C)

Updated on 20 October 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 20 October 2017 SmPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 6.4:
"Avoid exposure to excessive heat." added

Section 6.6

-    120 ml (2 bottles x 60 ml) with 2 x 2 ml syringes with 0.1 ml graduations
For volumes up to 2 ml.  For larger volumes an alternative pack is available.

-    300 ml (5 bottles x 60 ml) with 5 x 5 ml syringes with 0.1 ml graduations
For volumes greater than 2 ml.  For smaller volumes an alternative pack is available.

amended to:

     Multipack containing 120 ml (2 bottles of 60 ml) with 2 x 2 ml syringes with 0.1 ml graduations
For volumes up to 2 ml.  For larger volumes an alternative pack is available.

-    Multipack containing 300 ml (5 bottles of 60 ml) with 5 x 5 ml syringes with 0.1 ml graduations
For volumes greater than 2 ml.  For smaller volumes an alternative pack is available.

Updated on 20 October 2017 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 6 September 2017 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 5 September 2017 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 4.3 - Contraindications

 

Update to add new contraindications of lopinavir/ritonavir with venetoclax, with elbasvir/grazoprevir and with ombitasvir/paritaprevir/ritonavir with or without dasabuvir based on the company’s core data sheet;

The package Leaflet is updated accordingly

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

Update to the SmPC to reflect information already contained in section 4.3 for drug-drug interactions with astemizole, terfenadine, pimozide, ergot alkaloids and cisapride.

 

Section 10 – Date of Revision of Text

 

Updated to 08/2017

Updated on 3 August 2017 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 3 – Pharmaceutical Form
The solution is light yellow to orange.

Section 4.1 - Therapeutic indications
The therapeutic indication has been updated to read:

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children aged from 14 days and older.


Section 4.2 - Posology and method of administration

Posology and dosage recommendations for paediatric patients updated.

 

Section 4.4 - Special warnings and precautions for use

The following paragraph has been included at the end of this section:

 

Based on the findings in a paediatric study (observed exposures were approximately 35% AUC12 and 75% lower Cmin than in adults), young children from 14 days to 3 months could have sub-optimal exposure with a potential risk of inadequate virologic suppression and emergence of resistance (see section 5.2).

 

Because Kaletra oral solution contains alcohol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility.

 

Section 5.1          Pharmacodynamic properties

Information on Study P1030 included in tables 6, 7 and 8.

 

Section 5.2        Pharmacokinetic properties

Paediatric data updated.

 

Section 6.4 - Special precautions for storage

Avoid exposure to excessive heat has been deleted.

 

Section 6.5 - Nature and contents of container

Addition of a new pack size of 120 ml (2 x 60ml bottles) for Kaletra oral solution.

Addition of a new 2 ml oral dose syringe for the 120 ml pack size.

 

Section 8 - Marketing Authorisation Number

Addition of a new MA number

 

Section 10 – Date of Revision of Text

Updated to 07/2017





 

 

Updated on 2 August 2017 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 2 - excipient warnings
  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects

Updated on 8 June 2017 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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 6.1 -  List of excipients

·   “Heliotrope” has been updated to “heliotropin”

·   “Menthol” has been updated to “levomenthol”

 

 

Section 10 – Date of Revision of Text

 

·   Updated to 24 May 2017

Updated on 6 June 2017 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision

Updated on 26 September 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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

 

 

 

Ceritinib

Serum concentrations may be increased due to CYP3A and P‑gp inhibition by Kaletra.

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

Vorapaxar

Serum concentrations may be increased due to CYP3A inhibition by Kaletra.  Coadministration of vorapaxar and Kaletra is not recommended (see section 4.4 and refer to the vorapaxar SmPC).

Riociguat

Serum concentrations may be increased due to CYP3A and P-gp inhibition by Kaletra.  The coadministration of riociguat with Kaletra is not recommended (see section 4.4 and refer to riociguat SmPC).

 

 

 

 

 

 

 

Updated on 23 September 2016 PIL

Reasons for updating

  • Change to drug interactions

Updated on 30 August 2016 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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:
C
oncomitant 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

Updated on 24 August 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision

Updated on 3 March 2016 PIL

Reasons for updating

  • Change to drug interactions

Updated on 3 March 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 4.4
Information added regarding drug-drug interaction between delamanid and lopinavir/ritonavir:

"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.

Updated on 4 January 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

To update sections 4.4 and 4.8 of the SmPC  relating to information on lipodystrophy and metabolic parameters for HIV products

Updated on 24 December 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 28 September 2015 PIL

Reasons for updating

  • Change to drug interactions

Updated on 28 September 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 4.4

Addition of the following under the subsection "Interactioms with medicinal products":

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline Summary of Product Characteristics).


Section 4.5
Inclusion of Bedaquiline in interaction table.

Effects on drug levels:
A more pronounced effect on bedaquiline plasma exposures may be observed during prolonged co administration with lopinavir/ritonavir.  CYP3A4 inhibition likely due to lopinavir/ritonavir.

Clinical recommendation concerning co-administration with Kaletra:
Due to the risk of bedaquiline related adverse events, the combination of bedaquiline and lopinavir/ritonavir should be avoided. If the benefit outweighs the risk, co administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.4 and refer to the bedaquiline SmPC).

Updated on 13 August 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 7   MARKETING AUTHORISATION HOLDER
Update to address

Updated on 7 August 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to marketing authorisation holder

Updated on 28 November 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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

Updated on 26 November 2014 PIL

Reasons for updating

  • Change to instructions about missed dose
  • Change to drug interactions

Updated on 6 June 2014 PIL

Reasons for updating

  • Addition of information on reporting a side effect.

Updated on 13 May 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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.

Updated on 7 May 2014 PIL

Reasons for updating

  • Change to information about pregnancy or lactation

Updated on 20 January 2014 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 2:  Qualititative and Quantitiative Composition

 “Excipients” changed to “Excipients with known effect” (Kaletra Oral Solution Only)

Section 4.2 Posology and method of administration

The following additional text has been added to the section on Paediatric use (2 years of age and above), under Posology:

“If weight-based dosing is preferred, the dosage for patients greater than or equal to 15 kg to 40 kg is 10/2.5 mg/kg twice daily when Kaletra is not co-administered with nevirapine or efavirenz.”

The following information  has been added:

“The following tables contain dosing guidelines for Kaletra oral solution based on body weight and BSA.

 

Paediatric dosing guidelines based on body weight*

Body weight (kg)

Twice daily oral solution dose
(dose in mg/kg)

≥ 15 to 40 kg

10/2.5 mg/kg

            *weight based dosing recommendations are based on limited 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

 

“Each pack contains 5 bottles of 60ml (300ml)”  has been amended to “Multipacks containing 300 ml (5 bottles of 60 ml) oral solution”

 

Updated on 14 January 2014 PIL

Reasons for updating

  • Change of contraindications
  • Change to storage instructions
  • Change to drug interactions
  • Addition of information on reporting a side effect.

Updated on 6 September 2013 PIL

Reasons for updating

  • Change of distributor details

Updated on 5 June 2013 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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Section 5.1 (Pharmacodynamic properties)
Change to ATC Code

Updated on 18 March 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 15 March 2013 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

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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.

 

Updated on 14 November 2012 SmPC

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  • Change to section 7 - Marketing authorisation holder

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Marketing Authorisation Holder has been changed from Abbott to AbbVie.

Updated on 5 November 2012 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 21 September 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

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Section 4.5 of the SPC (Interactions) updated with information regarding the interaction of lopinavir/ritonavir and boceprevir. Section 4.5 (Interactions) has also been updated with information on the interactions of lopinavir/ritonavir and maraviroc, telaprevir, rivaroxaban, lamotrigine and valproate. The potential interaction of lopinavir/ritonavir and raltegravir is also addressed. In addition Section 4.4 of the SPC (Special warnings and precautions for use) has been updated with information regarding the interaction of lopinavir/ritonavir and budesonide

Updated on 14 September 2012 PIL

Reasons for updating

  • Change to drug interactions

Updated on 21 May 2012 PIL

Reasons for updating

  • Change to drug interactions
  • Change to how the medicine works

Updated on 1 May 2012 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.1 - List of excipients

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Sections 4.2 (Posology), 4.4 (Special Precautions for Use), 4.9 (Overdosage) and 5.2 (Pharmacokinetic Properties) have been updated in line with the latest Kaletra safety information.
Sections 2 and 6.1 have been updated to provide clarification on the qualitative and quantitative composition.

Updated on 13 July 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to side-effects
  • Change to date of revision

Updated on 12 July 2011 SmPC

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  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

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Section 4.5: Update to the information in section 4.5 of the SmPC on the interaction of lopinavir/ritonavir and rifabutin.

Updated on 6 May 2011 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

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Section 4.1:  The sentence:

"Kaletra is indicated for the treatment of HIV-1 infected adults and children above the age of 2 years, in combination with other antiretroviral agents." has been updated to read:

"Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 2 years."

Section 4.6 has been updated to read:

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

 

There are no adequate and well‑controlled studies of Kaletra in pregnant women.  In post‑marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among over 600 women exposed during the first trimester.  The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population.  No pattern of birth defects suggestive of a common etiology was seen.   Studies in animals have shown reproductive toxicity (see section 5.3).  Based on the limited data mentioned, the malformative risk is unlikely in humans.

 

 

Breastfeeding

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 mothers infected by HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.


Fertility
Animal studies have shown no effects on fertility.  No human data on the effect of lopinavir/ritonavir on fertility are available.



Updated on 5 April 2011 SmPC

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  • Change to section 9 - Date of renewal of authorisation

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Date of last renewal changed to 28 February 2011

Updated on 31 March 2011 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

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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."

Updated on 16 March 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

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

"The safety of Kaletra has been investigated in over 2600 patients in Phase II‑IV clinical trials, of which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily.  Along with NRTIs, in some studies, Kaletra was used in combination with efavirenz or nevirapine. "
Minor re-wording of other text
Section 5.1: "antivirals for systemic use" added to Pharmaco-therapeutic group.
Section 5.2: The sub-heading "Metabolism" changed to "Biotransformation".
Section 10: The following sentence added "Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu/ "

 

 

Updated on 28 October 2010 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions

Updated on 16 September 2010 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

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Section 4.1: Please see below track changes

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-1IIIB 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

 

Outcomes at Week 48: Study M98-863

 

Kaletra (N=326)

Nelfinavir (N=327)

HIV RNA < 400 copies/ml*

75%

63%

HIV RNA < 50 copies/ml*†

67%

52%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

207

195

* 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

 

Virologic Response of Study Subjects at Week 48 and Week 96

 

Week 48

Week 96

 

QD

BID

Difference

[95% CI]

QD

BID

Difference

[95% CI]

NC= Failure

257/333

(77.2%)

251/331

(75.8%)

1.3 %

[-5.1, 7.8]

216/333

(64.9%)

229/331

(69.2%)

-4.3%

[-11.5, 2.8]

Observed data

257/295

(87.1%)

250/280

(89.3%)

-2.2%

[-7.4, 3.1]

216/247

(87.4%)

229/248

(92.3%)

-4.9%

[-10.2, 0.4]

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

186

198

 

238

254

 

 

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

 

Outcomes at Week 360: Study M97-720

 

Kaletra (N=100)

HIV RNA < 400 copies/ml

61%

HIV RNA < 50 copies/ml

59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

501

 

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

 

Virologic Response of Study Subjects at Week 48 Study 802

 

QD

BID

Difference

[95% CI]

NC= Failure

171/300 (57%)

161/299 (53.8%)

3.2%

[-4.8%, 11.1%]

Observed data

171/225 (76.0%)

161/223 (72.2%)

3.8%

[-4.3%, 11.9%]

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

135

122

 

 

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

 

Outcomes at Week 48: Study M98-940

 

Antiretroviral Naïve (N=44)

Antiretroviral Experienced (N=56)

HIV RNA < 400 copies/ml

84%

75%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

404

284

Updated on 11 August 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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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)

Updated on 11 January 2010 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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Section 7 updated to change the registered address of the MA Holder from Queenborough, Kent, ME11 5EL, UK to Abbot House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, SL6 4XE, UK.
Consequential change to section 10.

Updated on 6 January 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to MA holder contact details

Updated on 18 December 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties

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Section 4.2 - renal impairment wording revised to improve consistency of the wording in response to a QRD comment made during assessment of the line extension application for Kaletra 100 mg/25 mg film-coated tablets (EMEA/H/C/368/X/42).

Section 4.3 - contraindication for use of lovastatin, simvastatin, sildenafil used for treatment of pulmonary arterial hypertension and vardenafil.

Section 4.4 - change to caution statement regarding PDE5 inhibitors.

Section 4.5 - reformat of section in line with Annex A to draft Guideline on Clinical Development of Medicinal Products for Treatment of HIV Infection (Presentation pharmacokinetic interaction data in the SPC) and update the safety information concerning the interaction of ritonavir, with tipranavir .

Section 5.1 - correction of an oversight that occurred during Type II variation EMEA/H/C/368/II/36, ie to update resistance information in section 5.1 of the SmPC with the 360 week data of Study M97-720.

Updated on 10 September 2009 SmPC

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  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Section 4.8 - section has been updated in accordance with new data

Section 5.2 - paragraph on "Absorption" has been updated with new values

- paragraph on "Absorption" has been updated with new values

Section 10 - Date of revision updated

- Date of revision updated

Updated on 25 November 2008 SmPC

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  • Change to section 5.1 - Pharmacodynamic properties
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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

 

Updated on 22 September 2008 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision

Updated on 10 September 2008 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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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 Cmin 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 Cmin (by 3.5-fold) and lower Cmax 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 Cmax 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) Cmax 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.

 

Undesirable eEffects in cClinical sStudies in aAdult pPatients

Infections and infestations

Uncommon

Otitis media, bronchitis, sinusitis, furunculosis, bacterial infections, viral infection

Neoplasms benignh, malignant and unspecified (including cysts and polyps)

 

Uncommon

Skin benign neoplasm, cyst

 

 

 

Blood and lymphatic system disorders

Uncommon

Anaemia, leucopenia and lymphadenopathy

Endocrine disorders

Uncommon

Hypergonadism male, Cushing syndrome, hypothyroidism

Metabolic and nutritional disorders

Uncommon

Avitminosis, dehydration, oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteramia

Phsychiatric disorders

Common

 

Uncommon

Insomnia

 

Abnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking

Nervous system disorders

Common

 

Uncommon

Headache, parathesia

 

Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste perversion, migraine, extrapyramidal syndrome

Euye disorder

Uncommon

Abnormal vision, eye disorder

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

Uncommon

Palpitation, lung oedema, myocardial infarc1

Vascular disorders

Uncommon

Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea, rhinitis, cough increased

Gastrointestinal disorders

Very common

 

Common

 

 

 

Uncommon

Diarrhoea

 

Nausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder

 

Abdomen enlarged, constipation, dry mouth, dysphagia, entercolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, panreatitis2, sialadenitis, stomatitis, ulcerative stomatitis, periedontitis

Hepatobiliary disorders

Uncommon

Cholecystitis, hepatitis, hepatomegaly, liver fatty deposit, liver tenderness

Skin and subcutaneous tissue disorders

Common

 

Uncommon

Rash, lipodystrophy, acne

 

Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder,

Pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae

Musculoskeletal and connective tissue disorder

Uncommon

Arthralgia, arthosis, myalgia, back pain, joint disorder

Renal and urinary disorders

Uncommon

Kidney calculus, urine abnormality, albuminuria, hypercalcinuria, hypericaemia

Reproductive system and breast disorders

Uncommon

Abnormal ejaculation, breast enlargement, gynecomastia, impotence, menorrhagia

General disorders and administration site conditions

Common

 

Uncommon

Asthemia, pain

 

Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction

Investigations

Very common

(Grade 3or 4)

 

Common

(Grade 3 or 4)

 

 

Uncommon

Increased triglycerides, increased total cholesterol, increased GGT

 

Increased glucose, increased amylase, increased SGOT/AST, increased SGPT/ALT, liver function tests abnormal

 

Decreased glucose tolerance, weight gain, weight loss, increased bilirubin, hormone level altered, lab test abnormal

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.

 

Undesirable eEffects in cClinical sStudies in pPaediatric pPatients

Infections and infestations

Common

Viral infection

 

Nervous system disorders

Common

Taste perversion

 

Gastrointestinal disorders

Common

Constipation, vomiting, pancreatitis*

 

Hepatobiliary disorders

Common

Hepatomegaly

 

Skin and subcutaneous tissue disorders

Common

Rash, dry skin

 

General disorders and administration site conditions

 

Common

Fever

Investigations

Common

(Grade 3 or 4)

Increased activated partial thromboplastin time, decreased haemoglobin, decreased platelets, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ALT, increased SGOT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils

 

 

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


 

Updated on 3 July 2008 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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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 2nd or 3rd 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

 

 

Updated on 5 December 2007 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to drug interactions
  • Change to date of revision

Updated on 29 November 2007 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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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

Updated on 1 November 2007 PIL

Reasons for updating

  • Change of trade or active ingredient name
  • Change to drug interactions
  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 30 October 2007 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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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 Cmax 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 Cmax 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.

 

 

Updated on 9 August 2007 PIL

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Updated on 6 August 2007 SmPC

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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.

Updated on 5 April 2007 PIL

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Updated on 3 April 2007 SmPC

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  • Change to section 4.8 - Undesirable effects
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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

 

Nervous system disorders

Common

 

Uncommon

 

Headache, paresthesia

 

Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, paresthesia, peripheral neuritis, somnolence, tremor, taste perversion, migraine, extrapyramidal syndrome

Skin and subcutaneous tissue disorders

Common

 

Uncommon

 

Rash, lipodystrophy, acne

 

Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder, pruritis, seborrhea, skin discoloration, skin ulcer, face oedema, acne, sweating, skin striae

General disorders and administration site conditions

 

 

 

Common

 

Uncommon

Asthenia, pain

 

Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, pain, peripheral oedema, drug interaction

 

 

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. 

 

 

Updated on 23 January 2007 PIL

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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).

 

Updated on 21 December 2006 PIL

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Updated on 12 December 2006 SmPC

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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 Cmin 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

 

 

Updated on 27 April 2006 SmPC

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Updated on 18 October 2005 SmPC

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Updated on 23 May 2005 PIL

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Updated on 19 April 2005 SmPC

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Updated on 10 August 2004 PIL

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Updated on 27 July 2004 SmPC

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Updated on 27 June 2003 SmPC

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