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

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

Dabigatran etexilate, Edoxaban

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

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

Drug-drug interaction between ritonavir and piroxicam removed.

Section 3

• Abbott logo removed from tablet

Section 4.4

The following paragraph has been removed:

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

Section 4.6

Breast-feeding section has been updated as follows:

Breast-feeding

Limited published data reports that ritonavir is present in human milk.

 "There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed infant, women living with HIV should not breast-feed their infants if they are receiving Norvir."

Section 4.5

Uodate to include information regarding drug drug interaction with fostamatinib

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

Minor editorial formating changes

Section 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 Norvir with lomitapide.
  
   

Section 10 - Date of Revision of the Text

• Updated to 04/2019

Section 4.2

Children and adolescents (2 years of age and above)

Updates made to reflect removal of Norvir Oral solution from marketing authorisation.  The Dosage conversion table refers to Norvir Powder for Oral Suspension instead of Norvir Oral Solution.

Section 4.5

Sub-section: Medicinal product that are affected by the use of ritonavir

The following statement has been removed:

“Norvir oral solution should not be co-administered with amprenavir oral solution to children due to the risk of toxicity from excipients in the two formulations”

Section 10

Date of Revision amended to 01 February 2019

Update to sections 4.4 and 4.8 to include autoimmune hepatitis.

Section 4.4

Immune Reconstitution Inflammatory Syndrome

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

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

 ---------------------

Section 4.8

Description of selected adverse reactions

 ------------
 

Metabolic parameters

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

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

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

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

Information added regarding the following interactions:

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

Section 10 Date of Revision of the Text

Updated to 13 September 2018

Section 4.3 - Contraindications

·         The list of medicinal products which Norvir 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 4.5 -  Interaction with other medicinal products and other forms of interaction

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

o    Ranolazine (Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected to increase.  The concomitant administration with ranolazine is contraindicated (see section 4.3).)

o    Lurasidone (Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected to increase.  The concomitant administration with lurasidone is contraindicated (see section 4.3).)

·    Information relating to Fluticasone propionate aqueous spray has been updated to read:

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

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression (plasma cortisol levels were noted to be decreased 86% in the above study) have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; similar effects could also occur with other corticosteroids metabolised by CYP3A e.g., budesonide and triamcinolone.  Consequently, concomitant administration of ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer 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 be required over a longer period.   

Section 10 – Date of Revision of Text

·    Updated to 02 June 2017

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:

Riociguat

The concomitant use of ritonavir is not recommended due to potiential increase in riociguat exposure (see section 4.5).

Vorapaxar

The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure (see section 4.5).

4.5          Interaction with other medicinal products and other forms of interaction

The following interactions have been added:

Afatinib

"Co‑administration of delamanid with a strong inhibitor of CYP3A (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 Summary of Product Characteristics)."

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



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

Description of Change - Drug - drug interaction (Simeprevir)

To update the SPC section, 4.4, according to CHMP request class label risk of sexual HIV transmission.
To update SPC in line with QRD V9

-          Section 4.2

“Elderly” replaced with “Older people”.

-          Section 4.3

Addition of the following contraindications:

“Quetiapine: Increased plasma concentrations of quetiapine which may lead to coma.  The concomitant administration with quetiapine is contraindicated (see section .4.5).”

“Avanafil: Increased plasma concentrations of avanafil (see section 4.4. and 4.5).”

“Vardenafil: Increased plasma concentrations of vardenafil (see section 4.4. and 4.5).”

-          Section 4.4

Addition of the following text under PDE5 inhibitors:

“Concomitant use of avanafil or vardenafil with ritonavir is contraindicated.”

-          Section 4.5

Under “Antipsychotics/Neuroleptics” addition of the following text:

“Quetiapine: Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected to increase.  Concomitant administration of Norvir and quetiapine is contraindicated as it may increase quetiapine-related toxicity.”

Under section “Phosphodiesterase (PDE5) inhibitors” addition of the following text:

“Avanafil: 50, single dose, 600 q12h, ↑ 13-fold, ↑ 2.4-fold. Concomitant use of avanafil with ritonavir is contraindicated (see section 4.3).”

Vardenafil:

Deleted text: “The concomitant use of vardenafil and ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should be with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions (see section 4.4).”

New text: “Concomitant use of vardenafil with ritonavir is contraindicated (see section 4.3).”

-          Section 4.8

Addition of the following text:

“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 6.5

Update of the wording of the pack size to the following:

“Multipack containing 450 ml (5 bottles of 90 ml)  oral solution plus five 7.5 ml dosing syringes.”

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

In section 7. Marketing Authorisation Holder

The previous name and address:

Abbott Laboratories Limited

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

Berkshire,

SL6 4XE     

United Kingdom

is changing to:

AbbVie Ltd

Maidenhead

SL6 4XE

United Kingdom

Under Section ‘4.4 Special warnings and precautions for use’ the following sentence has been added:

Rivaroxaban: It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased bleeding (see section 4.5).

Under Section ‘4.5 Interaction with other medicinal products and other forms of interaction’ the following information has been added to the tables:

In section 4.2 (Posology and Method of Administration) changes for administration with saquinavir, tipranavir and darunavir.

In section 4.4 (Special Warnings and Precautions for Use) updates regarding use with tenofovir disoproxil fumarate.

In section 4.8 (Undesirable Effects) the table has been updated for adverse reactions.