Prezista 100mg per ml suspension

  • Name:

    Prezista 100mg per ml suspension

  • 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: 20/05/20

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Summary of Product Characteristics last updated on medicines.ie: 15/5/2020

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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 20 May 2020 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

6.       Contents of the pack and other information

 

What PREZISTA contains

  • The active substance is darunavir. Each milliliter contains 100 milligram of darunavir (as ethanolate).
  • The other ingredients are hydroxypropylcellulose, microcrystalline cellulose and carmellose sodium, citric acid monohydrate, sucralose, strawberry cream flavour, masking flavour, sodium methyl parahydroxybenzoate (E219), hydrocholoric acid (for pH adjustment), purified water.
  • This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

 

What PREZISTA looks like and contents of the pack

White to off‑white opaque oral suspension. Provided in a 200 ml amber glass bottle with polypropylene child resistant closure and a 6 ml low density polyethylene (LDPE) oral dosing pipette with 0.2 ml gradations. The bottle neck is filled with a low density polyethylene (LDPE) insert that accommodates the dosing pipette. Do not use the oral dosing pipette for any other medicines.

PREZISTA is also available as 75 milligram, 150 milligram, 300 milligram, 400 milligram, 600 milligram and 800 milligram film‑coated tablets.

Updated on 15 May 2020 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 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

4.2          Posology and method of administration

PREZISTA oral suspension can be used in patients unable to swallow PREZISTA tablets. PREZISTA is also available as 75 mg, 150 mg, 300 mg, 400 mg, 600 mg and 800 mg film‑coated tablets.

 

4.4     Special warnings and precautions for use

 

Efavirenz in combination with boosted PREZISTA may result in sub‑optimal darunavir Cmin. If efavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg and 600 mg tablets (see section 4.5).

Updated on 11 March 2020 PIL

Reasons for updating

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

Free text change information supplied by the pharmaceutical company

zolpidem zoldipem

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

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
  • 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 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 5 November 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 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change in co-marketing arrangement

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 4.6 - Pregnancy and lactation
  • 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)

Free text change information supplied by the pharmaceutical company

Update to preganancy information. Warning that therapy with PREZISTA/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat should be switched to an alternative regimen.

Insufficient space in document history to add all text update.

Updated on 26 March 2018 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 4.9 - Overdose
  • 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

4.2     Posology and method of administration

 

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co‑administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate)fumarate or adefovir dipovoxil.

 

 

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 agents)

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

-                 ticagrelor (antiplatelets) (see section 4.5).

 

 

 

4.4     Special warnings and precautions for use

 

Interactions with medicinal products

Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co‑administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.

 

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 75 mg, 150 mg, 300 mg andor 600 mg tablets (see section 4.5).

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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.

 

PREZISTA co‑administered with cobicistat should not be used in combination with another antiretroviral that requires pharmacoenhancement since dosing recommendations for such combination have not been established.

 

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

300245 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 boosted PREZISTA is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

 

PREZISTA co‑administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.

Emtricitabine/tenofovir alafenamide

 

 

Tenofovir alafenamide

Tenofovir ↑

 

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

 

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

 

 

 

 

Amiodarone

Bepridil

Dronedarone

Lidocaine (systemic)

Quinidine

Ranolazine

Not studied. Boosted 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 boosted PREZISTA.

 

Boosted PREZISTA and amiodarone, bepridil, dronedarone, systemic lidocaine, quinidine, or ranolazine is contraindicated (see section 4.3).

 

Clonazepam

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

Clinical monitoring is recommended when co‑administering boosted PREZISTA and clonazepam.

 

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 combined with boosted PREZISTA. When co‑administration is required the daily dose of ketoconazole should not exceed 200 mg.

Fluconazole

Isavuconazole

Itraconazole

Posaconazole

 

 

 

 

Clotrimazole

Not studied. Boosted 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 boosted PREZISTA 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 boosted PREZISTA may increase plasma concentrations of darunavir and itraconazole.

(CYP3A and/or P‑gp inhibition)

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

Clotrimazole

Not studied. Concomitant systemic use of clotrimazole and boosted PREZISTA 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.

 

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 boosted PREZISTA and telaprevir.

 

Atorvastatin

10 mg once daily

atorvastatin AUC ↑ 3‑4 fold

atorvastatin Cmin5.5‑10 fold

atorvastatin Cmax ↑ ≈2 fold

#darunavir/ritonavir

 

atorvastatin AUC ↑ 290% Ω

atorvastatin Cmax ↑ 319% Ω

atorvastatin Cmin ND Ω

Ω with darunavir/cobicistat 800/150 mg

 

When administration of atorvastatin and boosted PREZISTA is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.

Pravastatin

40 mg single dose

pravastatin AUC ↑ 81%

pravastatin Cmin ND

pravastatin Cmax ↑ 63%

an up to five-fold increase was seen in a limited subset of subjects

When administration of pravastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.

Rosuvastatin

10 mg once daily

rosuvastatin AUC ↑ 48%

rosuvastatin Cmax ↑ 144%

based on published data with darunavir/ritonavir

 

rosuvastatin AUC ↑ 93%§

rosuvastatin Cmax ↑ 277%§

rosuvastatin Cmin ND§

§ with darunavir/cobicistat 800/150 mg

 

When administration of rosuvastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.

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)

H2‑RECEPTOR ANTAGONISTS

Ranitidine

150 mg twice daily

#darunavir AUC ↔

#darunavir Cmin

#darunavir Cmax

Boosted PREZISTA can be co‑administered with H2‑receptor antagonists without dose adjustments.

 

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 boosted PREZISTA with these analgesics.

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)

 

 

 

 

Ethinylestradiol

Norethindrone

35 mg/1 mg once daily

drospirenone AUC ↑ 58%

drospirenone Cmin ND

drospirenone Cmax ↑ 15%

ethinylestradiol AUC ¯ 30%

ethinylestradiol Cmin ND

ethinylestradiol Cmax ¯ 14%

with darunavir/cobicistat

 

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

Alternative or additional contraceptive measures are recommended when oestrogen‑based contraceptives are co‑administered with boosted PREZISTA.

 

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

 

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

 

 

 

 

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.

Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

 

10.     DATE OF REVISION OF THE TEXT

 

22 June 201715 February 2018

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 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 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 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 - how to report a side effect
  • Change to section 10 - Date of revision of the text

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

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$04.3     Contraindications$0$0 $0$0-                 elbasvir/grazoprevir (hepatitis C virus direct-acting antiviral)$0$0-                 lurasidone, pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)$0$0 $0$0 $0$04.5     Interaction with other medicinal products and other forms of interaction$0$0 $0$0 $0$0 $0$0 $0$0$0$0$0$0$0α1-ADRENORECEPTOR ANTAGONIST$0$0$0$0$0$0Alfuzosin$0$0$0$0Based on theoretical considerations PREZISTA is expected to increase alfuzosin plasma concentrations.$0$0(CYP3A inhibition)$0$0$0$0$0$0Co-administration of PREZISTA with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$0$0$0$0$0$0Risperidone$0$0Thioridazine$0$0 $0$0 $0$0 $0$0Lurasidone$0$0Pimozide$0$0Sertindole $0$0$0$0$0$0Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.$0$0(CYP3A, CYP2D6 inhibition and/or P‑gp)$0$0$0$0A dose decrease may be needed for these drugs when co‑administered with PREZISTA co‑administered with low dose ritonavir.$0$0 $0$0Concominant administration of PREZISTA with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$0 $0$0$0$0$0$0CORTICOSTEROIDS $0$0$0$0$0$0Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)Fluticasone$0$0Budesonide$0$0$0$0$0$0Fluticasone: 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.$0$0 $0$0Other 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. $0$0$0$0$0$0$0$0Concomitant 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. $0$0Co-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.$0$0Alternative 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.$0$0$0$0$0$0$0$0$0$0 $0$0$0$0$0$0$0Prednisone $0$0$0$0Not studied. Darunavir may increase plasma concentrations of prednisone.$0$0(CYP3A inhibition) $0$0$0$0$0$0Concomitant 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. $0$0$0$0$0$0$0 $0$0$0$0$0$0$0Elbasvir/grazoprevir$0$0$0$0PREZISTA with low dose ritonavir may increase the exposure to grazoprevir.$0$0(CYP3A and OATP1B inhibition)$0$0$0$0$0$0Concomitant use of PREZISTA with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$04.8     Undesirable effects$0$0 $0$0 $0$0Adverse reactions with darunavir/cobicistat in adult patients$0$0 $0$0$0$0$0$0$0Musculoskeletal and connective tissue disorders$0$0$0$0 $0$0$0$0$0$0common$0$0$0$0myalgia, osteonecrosis*$0$0 $0$0$0$0 $0$0$0$0$0$0uncommon$0$0$0$0osteonecrosis*$0$0$0$0$0$0$0$0$0$0$0$0

Updated on 3 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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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 14 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.

Option to use cobicistat as a booster in patients  18 years and older.

Addition drug-drug interactions

Adverse effects experienced with cobicistat combination

Updated on 12 November 2014 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
  • Changes to therapeutic indications

Updated on 28 March 2014 PIL

Reasons for updating

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

Updated on 27 March 2014 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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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

Reasons for updating

  • Change of contraindications
  • Change to date of revision

Updated on 23 October 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 10 - Date of revision of the text

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uodate to section 4.3 and 4.5 quetiapine contraindication

Updated on 26 September 2013 PIL

Reasons for updating

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

Updated on 26 September 2013 SmPC

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

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Approval of changes to Prezista suspension and Tablets SPC does not make a full combination SPC suitable.

Section 4.2 posology

ART‑naïve paediatric patients (12 to 17 years of age and weighing at least 40 kilograms).

The recommended dose regimen is PREZISTA 800 mg once daily with ritonavir 100 mg once daily taken with food.

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 with ritonavir 100 mg once daily taken with food may be used.

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

 

 

Administration of PREZISTA 800 mg once daily in treatment‑naïve adolescents 12 to 17 years weighing at least 40 kg leads to darunavir exposures within the therapeutic range as established in adults receiving the same dosing regimen. Since PREZISTA 800 mg once daily has also been registered for use in treatment‑experienced adults without darunavir resistance associated mutations (DRV‑RAMs)* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l, the same indication of PREZISTA 800 mg once daily applies to treatment‑experienced adolescents 12 to 17 years weighing at least 40 kg.

*    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

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 24 January 2013 PIL

Reasons for updating

  • Introduction of new strength

Updated on 7 November 2012 PIL

Reasons for updating

  • New PIL for new product