Prezista 600 mg film-coated tablets

  • Name:

    Prezista 600 mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    darunavir ethanolate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 09/05/19

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Summary of Product Characteristics last updated on medicines.ie: 10/5/2019

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Janssen Sciences Ireland

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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 10 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
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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
  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision

Updated on 27 November 2018 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 27 November 2018 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 medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.3     Contraindications

 

  • Added    dabigatran,
     
    4.5     Interaction with other medicinal products and other forms of interaction

 

ANTICOAGULANTS/PLATELET AGGREGATION INHIBITOR

Apixaban

Edoxaban

Dabigatran etexilate

Rivaroxaban

Not studied. Co‑administration of boosted PREZISTA with these anticoagulants may increase concentrations of the anticoagulant, which may lead to an increased bleeding risk.

(CYP3A and/or P‑gp inhibition)

The use of boosted PREZISTA and these anticoagulants is not recommended.

Dabigatran

Ticagrelor

Not studied. Coadministration with boosted PREZISTA may lead to a substantial increase in exposure to dabigatran or ticagrelor.

Concomitant administration of boosted PREZISTA with dabigatran or ticagrelor is contraindicated (see section 4.3).

 

Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.

 

 

 

 

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

 

NS3‑4A protease inhibitors

Glecaprevir/pibrentasvir

Based on theoretical considerations boosted PREZISTA may increase the exposure to glecaprevir and pibrentasvir.

(Pgp, BCRP and/or OATP1B1/3 inhibition)

It is not recommended to coadminister boosted PREZISTA with glecaprevir/pibrentasvir.

 

Updated on 31 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Removal/change of distributor

Updated on 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Removal/change of distributor

Updated on 29 October 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

Immune reactivation syndrome 

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

 

4.8     Undesirable effects 

Immune reconstitution inflammatory syndrome

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 these events can occur many months after initiation of treatment (see section 4.4).

Updated on 29 October 2018 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

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

 

Immune reactivation syndrome

 

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

 

Updated on 17 July 2018 PIL

Reasons for updating

  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 6 - date of revision

Updated on 17 July 2018 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 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 March 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 March 2018 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 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
  • Change from individual to joint SPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



NEW Combined SmPC

 

4.3          Contraindications

-                 alfuzosin (alpha 1‑adrenoreceptor antagonist)

-                 amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals)

-                 astemizole, terfenadine (antihistamines)

-                 colchicine when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)

-                 ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

-                 elbasvir/grazoprevir (hepatitis C virus direct-acting antiviral)

-                 cisapride (gastrointestinal motility agent)

-                 lurasidone, pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)

-                 triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see section 4.5)

-                 sildenafil ‑ when used for the treatment of pulmonary arterial hypertension, avanafil (PDE‑5 inhibitors)

-                 simvastatin,  and lovastatin and lomitapide (HMG‑CoA reductase inhibitors) (see section 4.5)

-                 ticagrelor (antiplatelets) (see section 4.5).

 

 

4.4          Special warnings and precautions for use

PREZISTA must always be given orally should only be used in combination with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with PREZISTA.

 

Efavirenz in combination with boosted PREZISTA/ritonavir 800/100 mg once daily may result in sub‑optimal darunavir Cmin. If efavirenz is to be used in combination with PREZISTA/ritonavir, the PREZISTA/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for PREZISTA 150 mg, 300 mg or 600 mg tablets  (see section 4.5).

 

Life‑threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P‑glycoprotein (P‑gp; see sections 4.3 and 4.5).

 

PREZISTA 300 mg tablets and 600 mg tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

 

Medicinal products that affect darunavir/ritonavir exposure

 

….Co‑administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, systemic azole antifungalss like ketoconazole and clotrimazole). These interactions are described in the interaction table below.

 

Elvitegravir

elvitegravir AUC ↔

elvitegravir Cmin

elvitegravir Cmax

darunavir AUC ↔

darunavir Cmin ↓ 17%

darunavir Cmax

 

 

 

 

 

When PREZISTA co‑administered with low dose ritonavir (600/100 mg twice daily) is used in combination with elvitegravir, the dose of elvitegravir should be 150 mg once daily.

 

The pharmacokinetics and dosing recommendations for other doses of darunavir or with elvitegravir/cobicistat have not been established. Therefore, co‑administration of PREZISTA with low dose ritonavir in doses other than 600/100 mg twice daily and elvitegravir is not recommended. Co‑administration of PREZISTA with low dose ritonavir and elvitegravir in the presence of cobicistat is not recommended.

 

 

 

Tenofovir disoproxil fumarate

300 245 mg once daily

 

tenofovir AUC ↑ 22%

tenofovir Cmin ↑ 37%

tenofovir Cmax ↑ 24%

#darunavir AUC ↑ 21%

#darunavir Cmin ↑ 24%

#darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR‑1 transport in the renal tubules)

Monitoring of renal function may be indicated when PREZISTA co‑administered with low dose ritonavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

Emtricitabine/tenofovir alafenamide

Tenofovir alafenamide  

Tenofovir ↑

 

 

 

The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with  PREZISTA with low dose ritonavir.

 

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

 

 

 

 

Amiodarone

Bepridil

Dronedarone

Lidocaine (systemic)

Quinidine

Ranolazine

 

 

Not studied. PREZISTA is expected to increase these antiarrhythmic plasma concentrations.

(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co‑administered with PREZISTA with low dose ritonavir.

 

PREZISTA co‑administered with low dose ritonavir and amiodarone, bepridil, dronedarone, systemic lidocaine, quinidine, or ranolazine is contraindicated (see section 4.3).

 

ANTIBIOTIC

Clarithromycin

500 mg twice daily

clarithromycin AUC ↑ 57%

clarithromycin Cmin ↑ 174%

clarithromycin Cmax ↑ 26%

#darunavir AUC ↓ 13%

#darunavir Cmin ↑ 1%

#darunavir Cmax ↓ 17%

14‑OH‑clarithromycin concentrations were not detectable when combined with PREZISTA/ritonavir.

(↑ clarithromycin from CYP3A inhibition and possible P‑gp inhibition)

Caution should be exercised when clarithromycin is combined with PREZISTA co‑administered with low dose ritonavir.

 

For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.

 

 

 

ANTICONVULSANTS

Phenobarbital

Phenytoin

Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.

(induction of CYP450 enzymes)

PREZISTA co‑administered with low dose ritonavir should not be used in combination with these medicines.

Carbamazepine

200 mg twice daily

carbamazepine AUC ↑ 45%

carbamazepine Cmin ↑ 54%

carbamazepine Cmax ↑ 43%

darunavir AUC ↔

darunavir Cmin ↓ 15%

darunavir Cmax

No dose adjustment for PREZISTA/ritonavir is recommended. If there is a need to combine PREZISTA/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine‑related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of PREZISTA/ritonavir.

Clonazepam

Not studied. Co‑administration of boosted PREZISTA with low dose ritonavir and clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)

Clinical monitoring is recommended when co‑administering PREZISTA with low dose ritonavir and clonazepam.

 

ANTIFUNGALS

Voriconazole

Not studied. Ritonavir may decrease plasma concentrations of voriconazole.

(induction of CYP450 enzymes by ritonavir)

Voriconazole should not be combined with PREZISTA co‑administered with low dose ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

Ketoconazole

200 mg twice daily

 

ketoconazole AUC ↑ 212%

ketoconazole Cmin ↑ 868%

ketoconazole Cmax ↑ 111%

#darunavir AUC ↑ 42%

#darunavir Cmin ↑ 73%

#darunavir Cmax ↑ 21%

(CYP3A inhibition)

 

 

 

 

 

 

Caution is warranted and clinical monitoring is recommended. When co‑administration is required the daily dose of ketoconazole should not exceed 200 mg.

Fluconazole

Isavuconazole

Itraconazole

Posaconazole

 

 

 

 

Clotrimazole

 

 

 

 

 

 

 

Not studied. PREZISTA may increase antifungal plasma concentrations (P‑gp inhibition) and posaconazole, isavuconazole, itraconazole, or fluconazole may increase darunavir concentrations.

(CYP3A and/or P‑gp inhibition)

 

Not studied. Concomitant systemic use of clotrimazole and darunavir co‑administered with low dose ritonavir may increase plasma concentrations of darunavir and/or clotrimazole.

darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)

 

 

 

 

 

Caution is warranted and clinical monitoring is recommended. When co‑administration is required the daily dose of itraconazole should not exceed 200 mg.

Itraconazole

Not studied. Concomitant systemic use of itraconazole and darunavir co‑administered with low dose ritonavir may increase plasma concentrations of darunavir and itraconazole. Simultaneously, plasma concentrations of itraconazole may be increased by darunavir co‑administered with low dose ritonavir.

(CYP3A and/or P‑gp inhibition)

 

Caution is warranted and clinical monitoring is recommended. When co‑administration is required the daily dose of itraconazole should not exceed 200 mg.

Clotrimazole

Not studied. Concomitant systemic use of clotrimazole and darunavir co‑administered with low dose ritonavir may increase plasma concentrations of darunavir and/or clotrimazole.

darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)

 

Caution is warranted and clinical monitoring is recommended, when co‑administration of clotrimazole is required.

ANTIGOUT MEDICINES

Colchicine

Not studied. Concomitant use of colchicine and darunavir co‑administered with low dose ritonavir may increase the exposure to colchicine.

(CYP3A and/ or P‑gp inhibition)

 

A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with PREZISTA co‑administered with low dose ritonavir is required. For pPatients with renal or hepatic impairment should not be given colchicine with PREZISTA co‑administered with low dose ritonavir is contraindicated (see sections 4.3 and 4.4).

 

Quetiapine

Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.

(CYP3A inhibition)Due to CYP3A inhibition by darunavir, concentrations of the antipsychotics/neuroleptics are expected to increase.

Concomitant administration of PREZISTA with low dose ritonavir and quetiapine is contraindicated as it may increase quetiapine‑related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).

Perphenazine

Risperidone

Thioridazine

 

 

 

Lurasidone

Pimozide

Sertindole

Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.

(CYP3A, CYP2D6 inhibition and/or P‑gp inhibition)

A dose decrease may be needed for these drugs when co‑administered with PREZISTA co‑administered with low dose ritonavir.

 

Concominant administration of PREZISTA with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).

 

Bosentan

Not studied. Concomitant use of bosentan and PREZISTAdarunavir co‑administered with low dose ritonavir may increase plasma concentrations of bosentan.

Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.

(CYP3A induction)

 

 

When administered concomitantly with PREZISTA and low dose ritonavir, the patient’s tolerability of bosentan should be monitored.

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

NS3‑4A protease inhibitors

Elbasvir/grazoprevir

PREZISTA with low dose ritonavir may increase the exposure to grazoprevir.

(CYP3A and OATP1B inhibition)

Concomitant use of PREZISTA with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).

Telaprevir

750 mg every 8 hours

 

telaprevir AUC ↓ 35%

telaprevir Cmin ↓ 32%

telaprevir Cmax ↓ 36%

darunavir AUC12 ↓ 40%

darunavir Cmin ↓ 42%

darunavir Cmax ↓ 40%

 

 

 

 

 

It is not recommended to co‑administer PREZISTA with low dose ritonavir and telaprevir

 

OTHER LIPID MODIFYING AGENTS

Lomitapide

Based on theoretical considerations boosted PREZISTA is expected to increase the exposure of lomitapide when co-administered.

(CYP3A inhibition)

 

Co-administration is contraindicated (see section 4.3)

 

Fentanyl

Oxycodone

Tramadol

 

 

Based on theoretical considerations boosted PREZISTA may increase  plasma concentrations of these analgesics.

(CYP2D6 and/or CYP3A inhibition)

 

Clinical monitoring is recommended when co‑administering PREZISTA with low dose ritonavir with these analgesics.

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)

 

 

 

 

Ethinylestradiol

Norethindrone

35 mg/1 mg once daily

 

 

 

 

 

Not studied with darunavir/ritonavir.

 

 

 

 

 

 

 

ethinylestradiol AUC ↓ 44%β

ethinylestradiol Cmin ↓ 62%β

ethinylestradiol Cmax ↓ 32%β

norethindrone AUC ↓ 14%β

norethindrone Cmin 30%β

norethindrone Cmaxβ

β with darunavir/ritonavir

 

 

 

 

 

 

 

 

 

 

 

 

 

When PREZISTA is coadministered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.

 

Alternative or additional contraceptive measures are recommended when oestrogen‑based contraceptives are co‑administered with PREZISTA and low dose ritonavir.

 

Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

 

 

 

 

 

 

 

 

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)Triazolam

Zoldipem

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Midazolam (oral)

Triazolam

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co‑administration with PREZISTA/ritonavir may cause a large increase in the concentration of these medicines.

 

 

 

 

 

Based on data for other CYP3A inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally with PREZISTA co‑administered with low dose ritonavir.

 

 

 

If parenteral midazolam is co‑administered with PREZISTA co‑administered with low dose ritonavir it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3‑4 fold increase in midazolam plasma levels.

 

 

 

 

 

 

Clinical monitoring is recommended when co‑administering PREZISTA with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered. PREZISTA co‑administered with low dose ritonavir is contraindicated with triazolam.

 

PREZISTA co‑administered with low dose ritonavir is contraindicated with orally administered midazolam (see section 4.3); whereas, caution should be used with co‑administration of PREZISTA with low dose ritonavir and parenteral midazolam.

 

If parenteral midazolam is co‑administered with PREZISTA with a low dose ritonavir, 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. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

 

PREZISTA with low dose ritonavir with triazolam or oral midazolam is contraindicated (see section 4.3)

 

 

 

 

4.9     Overdose

 

 

There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.  If indicated, elimination of unabsorbed active substance is to be achieved by emesis.

 

10.     DATE OF REVISION OF THE TEXT

 

22 June 2017 15 February 2018

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 23 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 23 March 2018 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 10 July 2017 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

Dolutegravir:

dolutegravir AUC ↓ 3222%

dolutegravir C24h 38%

dolutegravir Cmax ↓ 11%

darunavir ↔*

* Using cross_study comparisons to historical pharmacokinetic data

 

Elvitegravir:

elvitegravir AUC ↔

elvitegravir Cmin ↔

elvitegravir Cmax ↔

darunavir AUC ↔

darunavir Cmin 17%

darunavir Cmax ↔

 

Section 5.2: Pharmacokinetic properties

 

Table: Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum

 

b     excluding Cmin value below LLOQ, n=10 for reference postpartum

 

Updated on 27 March 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 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

.3       Contraindications

 

-                 elbasvir/grazoprevir (hepatitis C virus direct-acting antiviral)

-                 lurasidone, pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

 

Ritonavir inhibits the transporters P‑glycoprotein, OATP1B1 and OATP1B3, and co‑administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

 

 

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Based on theoretical considerations PREZISTA is expected to increase alfuzosin plasma concentrations.

(CYP3A inhibition)

Co-administration of PREZISTA with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).

 

Risperidone

Thioridazine

 

 

 

Lurasidone

Pimozide

Sertindole

Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.

(CYP3A, CYP2D6 inhibition and/or P‑gp)

A dose decrease may be needed for these drugs when co‑administered with PREZISTA co‑administered with low dose ritonavir.

 

Concominant administration of PREZISTA with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).



CORTICOSTEROIDS

Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)Fluticasone

Budesonide

Fluticasone: Iin a clinical study where ritonavir 100 mg capsules twice daily were co‑administered with 50 mg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82‑89%). Greater effects may be expected when fluticasone 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; this could also occur with other corticosteroids metabolised via the P4503A pathway, e.g., budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.

 

Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with PREZISTA with low dose ritonavir, resulting in reduced serum cortisol concentrations.

Concomitant use of PREZISTA with low dose ritonavir and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.

Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long term use.Concomitant administration of PREZISTA co‑administered with low dose ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. 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 CYP3A (e.g., beclomethasone). Moreover, in case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.

 

Prednisone

Not studied. Darunavir may increase plasma concentrations of prednisone.

(CYP3A inhibition)

Concomitant use of PREZISTA with low dose ritonavir and prednisone may increase the risk for development of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Clinical monitoring is recommended when co‑administering PREZISTA with low dose ritonavir with corticosteroids.

 

Elbasvir/grazoprevir

PREZISTA with low dose ritonavir may increase the exposure to grazoprevir.

(CYP3A and OATP1B inhibition)

Concomitant use of PREZISTA with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).



Updated on 27 March 2017 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 2 February 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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$04.4     Special warnings and precautions for use$0$0 $0$0Diabetesmellitus/hyperglycaemia$0$0New onset diabetes mellitus, hyperglycaemia, orexacerbation of existing diabetes mellitus has been reported in patientsreceiving antiretroviral therapy, including PIs. In some of these patients thehyperglycaemia was severe and in some cases also associated with ketoacidosis.Many patients had confounding medical conditions some of which required therapywith agents that have been associated with the development of diabetes mellitusor hyperglycaemia.$0$0 $0$0Fatredistribution and metabolic disorders$0$0Combination antiretroviral therapy has beenassociated with redistribution of body fat (lipodystrophy) in HIV infectedpatients. The long‑term consequences of these events are currently unknown.Knowledge about the mechanism is incomplete. A connection between viscerallipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higherrisk of lipodystrophy has been associated with individual factors such as olderage and with drug related factors such as longer duration of antiretroviraltreatment and associated metabolic disturbances. Clinical examination shouldinclude evaluation for physical signs of fat redistribution. Considerationshould be given to measurement of fasting serum lipids and blood glucose. Lipiddisorders should be managed as clinically appropriate (see section 4.8).$0$0 $0$0Weight and metabolic parameters$0$0An increase in weight and in levels of blood lipidsand glucose may occur during antiretroviral therapy. Such changes may in partbe linked to disease control and life style. For lipids, there is in some casesevidence for a treatment effect, while for weight gain there is no strongevidence relating this to any particular treatment. For monitoring of bloodlipids and glucose reference is made to established HIV treatment guidelines.Lipid disorders should be managed as clinically appropriate.$0$0 $0$0 $0$0 $0$04.8     Undesirable effects$0$0 $0$0$0$0$0$0Metabolism andnutrition disorders$0$0$0$0$0$0common$0$0$0$0lipodystrophy (including lipohypertrophy,lipodystrophy, lipoatrophy), diabetes mellitus,hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia$0$0 $0$0$0$0$0$0uncommon$0$0$0$0gout, anorexia, decreased appetite, decreased weight,increased weight, hyperglycaemia, insulin resistance, decreased high densitylipoprotein, increased appetite, polydipsia, increased blood lactatedehydrogenase$0$0$0$0$0$0 $0$0 $0$0 $0$0Lipodystrophy$0$0Combination antiretroviral therapy has beenassociated with redistribution of body fat (lipodystrophy) in HIV patients,including loss of peripheral and facial subcutaneous fat, increased intra‑abdominaland visceral fat, breast hypertrophy and dorsocervical fat accumulation(buffalo hump) (see section 4.4).$0$0 $0$0Metabolicabnormalities$0$0Combination antiretroviral therapy has also beenassociated with metabolic abnormalities such as hypertriglyceridaemia,hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia(see section 4.4).$0$0 $0$0Metabolic parameters$0$0Weight and levels of blood lipids and glucose mayincrease during antiretroviral therapy (see section 4.4).$0$0 $0

Updated on 1 February 2016 PIL

Reasons for updating

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

Updated on 27 October 2015 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 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
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addition in red text 

 

4.2     Posology and method of administration

 

 

Pregnancy and postpartum

No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Prezista should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).

 

4.4     Special warnings and precautions for use

 

 

Pregnancy

Prezista should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).

 

4.6     Fertility, pregnancy and lactation

 

 

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.

 

There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

 

PREZISTA co‑administered with cobicistat or low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.

 

4.8     Undesirable effects

 

uncommon

immune reconstitution inflammatory syndrome, (drug) hypersensitivity

 

 

 

5.1     Pharmacodynamic properties

 

 

Pregnancy and postpartum

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 34 pregnant women (17 in each arm) during the second and third trimesters, and postpartum. Virologic response was preserved throughout the study period in both arms. No mother to child transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV 1 infected adults (see sections 4.2, 4.4 and 5.2).

 

5.2     Pharmacokinetic properties

 

Pregnancy and postpartum

The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

 

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of total darunavir

(mean ± SD)

Second trimester of pregnancy

(n=11)a

Third trimester of pregnancy

(n=11)

Postpartum (6‑12 weeks)

(n=11)

Cmax, ng/ml

4,601 ± 1,125

5,111 ± 1,517

6,499 ± 2,411

AUC12h, ng.h/ml

38,950 ± 10,010

43,700 ± 16,400

55,300 ± 27,020

Cmin, ng/mlb

1,980 ± 839.9

2,498 ± 1,193

2,711 ± 2,268

a    n=10 for AUC12h

b    excluding Cmin value below LLOQ, n=10 for reference

 

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of total darunavir

(mean ± SD)

Second trimester of pregnancy

(n=16)

Third Trimester of pregnancy

(n=14)

Postpartum (6‑12 weeks)

(n=15)

Cmax, ng/ml

4,988 ± 1,551

5,138 ± 1,243

7,445 ± 1,674

AUC12h, ng.h/ml

61,303 ± 16,232

60,439 ± 14,052

94,529 ± 28,572

Cmin, ng/mla

1,193 ± 509

1,098 ± 609

1,572 ± 1,108

a    n=12 for postpartum, n=15 for second trimester and n=14 for third trimester

 

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra‑individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 24% and 17% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 19%, 17% lower and 2% higher, respectively, as compared with postpartum.

 

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra‑individual values for total darunavir Cmax, AUC12h and Cmin were 34%, 34% and 32% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 31%, 35% and 50% lower, respectively, as compared with postpartum.

 

Updated on 22 October 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change of distributor details

Updated on 13 November 2014 SmPC

Reasons for updating

  • 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 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Major revision of SmPC,

Notable changes once daily dosing in Paediatrics.


Addition drug-drug interactions

Updated on 12 November 2014 PIL

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  • 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 28 March 2014 PIL

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

Updated on 27 March 2014 SmPC

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

 

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.

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Updated on 20 December 2013 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 24 October 2013 PIL

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  • Change of contraindications
  • Change to date of revision

Updated on 23 October 2013 SmPC

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

Updated on 30 September 2013 PIL

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  • Change to side-effects
  • Change to date of revision
  • Change to drug interactions
  • Change to dosage and administration

Updated on 27 September 2013 SmPC

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  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
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4.2 posology -addition

For dosage recommendations in paediatric patients 12 to 17 years of age and weighing at least 40 kg with prior exposure to antiretroviral medicinal products but without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l a dose regimen of 800 mg once daily may be used (see Summary of Product Characteristics of the PREZISTA 100 mg/ml oral suspension, and PREZISTA 400 mg and 800 mg tablets).

*    DRV‑RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

4.4          Special warnings and precautions for use

 

Severe skin reactions

During the clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens‑Johnson Syndrome has been rarely (< 0.1%) reported, and during post‑marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported.

 4.8 undesirable effects – change to frequency category for some ADRs

Addition of DRESS and reporting ADR statements

Updated on 11 June 2013 PIL

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  • Change to warnings or special precautions for use

Updated on 10 June 2013 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
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Implement class labeling with respect to Immune Reconstitution Syndrome (IRS).

Updated on 24 January 2013 PIL

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  • Introduction of new strength

Updated on 23 January 2013 SmPC

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

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Inclusion of Raltegravir interactions
New 800mg strength tablet

Updated on 7 November 2012 SmPC

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  • 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 4.9 - Overdose
  • Change to section 5 - Pharmacological properties
  • 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 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling

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New formulation - Prezista oral suspension 100mg/ml
Extended paediatric indication
Inclusion of interactions with antimalarials

Updated on 7 November 2012 PIL

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  • Change to dosage and administration
  • Change to improve clarity and readability

Updated on 7 September 2012 SmPC

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  • Change to section 6.3 - Shelf life

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Increase in shelf life from 2 to 3 years

Updated on 12 July 2012 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
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Addition of acute generalised exanthematous pustulosis (AGEP) as an adverse drug reaction.

Updated on 20 April 2012 SmPC

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

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Addition of Boceprevir interaction.

Updated on 18 April 2012 PIL

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  • Change to drug interactions

Updated on 6 March 2012 PIL

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  • Change to drug interactions

Updated on 6 March 2012 SmPC

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

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Addition of Rilpivirine and Telaprevir interactions.

Updated on 5 August 2011 SmPC

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  • Change to section 4.8 - Undesirable effects
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Section 4.8

In the 96 week analysis, the safety profile of PREZISTA/rtv 800/100 mg once daily in treatment‑naïve subjects was similar to that seen with PREZISTA/rtv 600/100 mg twice daily in treatment‑experienced subjects except for nausea which was observed more frequently in treatment‑naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment‑naive subjects in which the mean treatment duration of PREZISTA/rtv 800/100 mg once daily was 162.5 weeks.



Section 5.1

Efficacy of PREZISTA 800 mg once daily coadministered with 100 mg ritonavir once daily in ART‑naïve patients

The evidence of efficacy of PREZISTA/ritonavir 800/100 mg once daily is based on the analyses of 96192 week data from the randomised, controlled, open‑label Phase III trial ARTEMIS in antiretroviral treatment‑naïve HIV‑1 infected patients comparing PREZISTA/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a twice‑daily or as a once‑daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and emtricitabine 200 mg once daily.


-------

Non‑inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the percentage of patients with plasma HIV‑1 RNA level < 50 copies/ml, was demonstrated (at the pre‑defined 12% non‑inferiority margin) for both Intent‑To‑Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Updated on 3 August 2011 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 13 June 2011 SmPC

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  • 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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Change to section 4.5 - addition of Rosuvastatin
Change to section 10 - May 2011

Updated on 8 June 2011 PIL

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  • Change to drug interactions
  • Change to date of revision

Updated on 23 March 2011 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision
  • Change to dosage and administration

Updated on 10 March 2011 SmPC

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  • 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 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 of the SmPC has been updated with information regarding the once daily dosing regime for treatment-experienced patients:

For ARTexperienced adults with no darunavir resistance associated mutations (DRVRAMs)* and who have plasma HIV1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l, a dose regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used .


Section 5 of the SmPC has been updated with the relevant clinical trial information:

 ODIN
is a Phase III, randomised, open‑label trial comparing PREZISTA/rtv 800/100 mg once daily versus PREZISTA/rtv 600/100 mg twice daily in ART‑experienced HIV‑1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV1 RNA > 1,000 copies/ml. Efficacy analysis is based on 48 weeks of treatment

Updated on 9 December 2010 PIL

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

Updated on 9 December 2010 SmPC

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  • 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
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Section 4.3 Contra-indications

Addition of sildenafil when used for treatment of pulmonary hypertension.

Section 4.4 Special warnings

Warning added for life threatening/fatal drug interactions in patients treated with colchicine and strong inhibitors of CYP3A and Pgp.

Section 4.5 Interactions

Addition of information for sildenafil (when used for pulmonary hypertension), colchicine, bosentan, salmeterol.

Updated on 3 August 2010 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
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Addition of contra-indication for alfuzosin to section 4.3
Addition of a warning to sections 4.4 and 4.8 regarding the potential for a higher than expected rate of rash when raltegravir is co-administered with Prezista (in line with the Isentress label).
Addition of a statement to section 4.5 regarding rifabutin dose reduction.
 Change to date of revision.

Updated on 30 July 2010 PIL

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

Updated on 22 June 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
  • Change to joint SPC covering all presentations

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Change to section 4.4 - Special warnings and precautions for use

Reformatting as per new SmPC guidance, and additional information regarding hepatotoxicity.

Change to section 4.8 - Undesirable effects

Reformatting as per new SmPC guidance.

Change to section 10 - Date of revision of the text

02.06.10

Change to joint SPC covering all presentations

 

Updated on 16 June 2010 PIL

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

Updated on 19 November 2009 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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4.5

Interaction with other medicinal products and other forms of interaction

Addition of buprenorphine/naloxone DDI

5.1

Pharmacodynamic properties

Addition of 96 week trial data (ARTEMIS & TITAN trials)

10.

DATE OF REVISION OF THE TEXT

 

 23.10.09

 

Updated on 12 November 2009 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision

Updated on 21 August 2009 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 31 July 2009 SmPC

Reasons for updating

  • New SPC for new product

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None provided

Updated on 1 July 2009 PIL

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  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Change to dosage and administration

Updated on 11 February 2009 PIL

Reasons for updating

  • New PIL for new product