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Vitekta (elvitegravir) – Summary of product characteristics - J05AX11

Updated on site: 10-Oct-2017

Medication nameVitekta
ATC CodeJ05AX11
Substanceelvitegravir
ManufacturerGilead Sciences International Ltd
Film-coated tablet (tablet).
For the full list of excipients, see section 6.1.
Each film-coated tablet contains 85 mg of elvitegravir.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Vitekta 85 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient with known effect: Each tablet contains 6.2 mg lactose (as monohydrate)authorised.

3. PHARMACEUTICAL FORM

Green, pentagon-shaped, film-coated tablet of dimensionslonger8.9 mm x 8.7 mm, debossed with “GSI” on one side of the tablet and “85” on the other side of the tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

product

no

Vitekta co-administered with a ritonavir-boos ed protease inhibitor and with other antiretroviral

agents, is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults

who are infected with HIV-1 witho t known mutations associated with resistance to elvitegravir (see sections 4.2 and 5.1).

4.2 Posology and meth d f a ministration

Therapy should be initiated by a physician experienced in the management of HIV infection.

MedicinalPosology

Vitekta must be dministered in combination with a ritonavir-boosted protease inhibitor.

The Summary of Product Characteristics for the co-administered ritonavir-boosted protease inhibitor should be onsulted.

The recommended dose of Vitekta is one 85 mg tablet or one 150 mg tablet taken orally once daily with food. The choice of dose of Vitekta depends on the co-administered protease inhibitor (see Table 1 and sections 4.4 and 4.5). For use of the 150 mg tablet, please refer to the Summary of Product Characteristics for Vitekta 150 mg tablets.

Vitekta should be administered once daily as follows:

-Either at the same time as a once daily ritonavir-boosted protease inhibitor

-Or with the first dose of a twice daily ritonavir-boosted protease inhibitor.

antimycobacterials: rifampicin
herbal products: St. John’s wort (Hypericum perforatum)
3

Table 1: Recommended dosing regimens

Dose of Vitekta

Dose of co-administered ritonavir-boosted protease inhibitor

 

85 mg once daily

atazanavir 300 mg and ritonavir 100 mg once daily

 

 

 

lopinavir 400 mg and ritonavir 100 mg twice daily

 

 

 

 

 

 

150 mg once daily

darunavir 600 mg and ritonavir 100 mg twice daily

 

 

 

fosamprenavir 700 mg and ritonavir 100 mg twice daily

 

 

 

 

If the patient vomits within 1 hour

of taking Vitekta another tablet should beauthorisedtaken.

 

There are no data to recommend the use of Vitekta with dosing frequencies or HIV-1 protease inhibitors other than those presented in Table 1.

Missed dose

If the patient misses a dose of Vitekta within 18 hours of the time it is usually taken, e patient should take Vitekta with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Vitekta by more than 18 hours, and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

Special populations

longer

 

Elderly

No data are available on which to make a dose recommendati n for patients over the age of 65 years (see section 5.2).

Renal impairment

 

No dose adjustment of Vitekta is required for patie ts with renal impairment (see section 5.2).

Hepatic impairment

no

 

hepatic impairment (Child-Pugh Class C) (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of elvitegravir in children aged 0 to less than 18 years have not yet been

No dose adjustment of productVitekta is req ired in patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). Elvitegravir has not been studied in patients with severe

established (see section 5.1). No data are available. MedicinalMethod of admi istr tion

Vitekta should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not be hewed or crushed.

4.3 Contraindications

Hyp rsensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with the following medicinal products due to the potential for loss of virologic

response and possible development of resistance (see section 4.5):

anticonvulsants: carbamazepine, phenobarbital, phenytoin

4.4 Special warnings and precautions for use

General

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

The use of Vitekta with HIV-1 protease inhibitors or dosing frequencies other than those presented in

Table 1 may result in inadequate or elevated plasma levels of elvitegravir and/or the co-administered

medicinal products.

authorised

 

Resistance

Elvitegravir-resistant viruses show cross-resistance to the integrase strand transfer inhibitor raltegravir in most cases (see section 5.1).

Elvitegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, Vitekta should be administered with a fully active ritonavir-boosted protease inhibitor and a second fully active antiretroviral agent to minimise the potential for virologic failure and the development of resistance (see section 5.1).

Co-administration of other medicinal products

longer

 

Elvitegravir is primarily metabolised by CYP3A. Co-administration of Vit kta with strong CYP3A inducers (including St. John’s wort [Hypericum perforatum], rifampicin, carbamazepine, phenobarbital and phenytoin) is contraindicated (see sections 4.3 and 4.5). Co-administration of Vitekta with moderate CYP3A inducers (including, but not limited to, efavirenz and bosentan) is not recommended (see section 4.5).

Due to the need for co-administration of Vitekta with a ritonavir-boosted protease inhibitor,

inhibitor and ritonavir for a description of co trainodicated medicinal products and other significant drug-drug interactions that may cause po en ially life-threatening adverse reactions or loss of therapeutic effect and possible development of resistance.

prescribers should consult the Summary of Product Characteristics of the co-administered protease

Atazanavir/ritonavir and lopinavir/ritonavir have been shown to significantly increase the plasma concentrations of elvitegravir (see section 4.5). When used in combination with atazanavir/ritonavir

and lopinavir/ritonavir, the d se f Vitekta should be decreased from 150 mg once daily to 85 mg once

daily (see section 4.2).

Co-administration of Vitekta and related active substances: Vitekta must be used in combination with

 

product

a ritonavir-boosted protease inhibitor. Vitekta should not be used with a protease inhibitor boosted by

another agent s dosing recommendations for such combinations have not been established. Boosting

elvitegrav r w th

 

gent other than ritonavir may result in suboptimal plasma concentrations of

Medicinal

 

elvitegrav r a d/or the protease inhibitor leading to loss of therapeutic effect and possible development of res stan e.

Vitekta should not be used in combination with products containing elvitegravir or pharmacokinetic boosting agents other than ritonavir.

Contraception requirements

Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 µg ethinylestradiol and containing norgestimate as the progestagen or should use an alternative reliable method of contraception (see sections 4.5 and 4.6). Co-administration of elvitegravir with oral contraceptives containing progestagens other than norgestimate have not been studied and, therefore, should be avoided.

Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency (see section 4.5).

Opportunistic infections

Patients receiving Vitekta or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Patients with HIV and hepatitis B or C virus co-infection

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV).

Liver disease

Elvitegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). No dose adjustment of Vitekta is required in patients with mild (Child-Pugh Class A) or m derate hepatic impairment (Child-Pugh Class B) (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, h ve an increased

authorised

frequency of liver function abnormalities during combination antiretrovir l ther py (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be consid d.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease c tr l a d life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating

this to any particular treatment. For monitoring

f bl d ipids and glucose reference is made to

established HIV treatment guidelines. Lipid dis

longer

rders should be managed as clinically appropriate.

Immune Reactivation Syndrome

no

 

In HIV infected patients with severe immune deficiency at the time of institution of CART, an

inflammatory reaction toproductasymptomatic or residual opportunistic pathogens may arise and cause

serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or f cal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms sh uld be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of Medicinalimmune reactivation; however, the reported time to onset is more variable and these events can occur

many months fter initiation of treatment.

Osteone ros s

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumpt on, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Pati nts should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Excipients

Vitekta contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Interactions with CYP3A inducers

Elvitegravir is primarily metabolised by CYP3A (see section 5.2). Medicinal products that are strong (causing a > 5-fold increase in substrate clearance) or moderate (causing a 2-5 fold increase in substrate clearance) inducers of CYP3A are expected to decrease plasma concentrations of elvitegravir.

Concomitant use contraindicated

Concomitant use not recommended

Co-administration of Vitekta with medicinal products that are strong inducers of CYP3A is contraindicated as the expected decrease in plasma concentrations of elvitegravirauthorisedcan lead to loss of therapeutic effect and possible development of resistance to elvitegravir (see section 4.3).

Co-administration of Vitekta with medicinal products that are moderate inducers of CYP3A

(including, but not limited to, efavirenz and bosentan) is not recommended as the expected dec ease in plasma concentrations of elvitegravir can lead to loss of therapeutic effect and possible devel pment of resistance to elvitegravir (see section 4.4).

Interactions requiring dose adjustment of Vitekta

modifications may be required. For example, atazanavir/ritonavir and lopinavir/ritonavir (potent UGT1A1/3 inhibitors) have been shown to significantly increase the plasma concentrations of

Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation by UGT1A1/3 enzymes (minor route). Co-administration of Vitekta with medicinal products that are potent inhibitors of UGT1A1/3 may result in increased elvitegravirlongerplasma concentrations and dose

elvitegravir (see Table 2). Accordingly, when used in combi ation with atazanavir/ritonavir and lopinavir/ritonavir, the dose of Vitekta should be decreased fr m 150 mg once daily to 85 mg once daily (see sections 4.2 and 4.4).

Other interactionsno

elvitegravir is a weak to modest ind er of CYP1A2, CYP2C19 and CYP3A enzymes. Elvitegravir would also have potential to be a weak to modest inducer of CYP2B6 and CYP2C8 enzymes, as these enzymes are regulated in a similar manner to CYP2C9 and CYP3A. However, clinical data have shown there are no clinically relevant changes in the exposure of methadone (which is primarily metabolised by CYP2B6 and CYP2C19) following co-administration with boosted elvitegravir versus administration of methadone alone (see Table 2).

Elvitegravir is a modest inducer and may have the potential to induce CYP2C9 and/or inducible UGT enzymes. As such, elvitegravirproductmay decrease he plasma concentration of substrates of CYP2C9 (such as warfarin) or UGT (such as ethinyl estradiol). In addition, in vitro studies have shown that

MedicinalElvitegravir is a substrate for OATP1B1 and OATP1B3, and an inhibitor of OATP1B3 in vitro. The in vivo relevance of these interactions is not clear.

Intera t o s between elvitegravir and potential co-administered medicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). These interactions are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

Wh re interactions were studied, the effect on Vitekta was determined by comparing the pharmacokinetics of boosted elvitegravir (using either ritonavir or cobicistat as a pharmacokinetic enhancer) in the absence and presence of the co-administered medicinal product. No interactions were studied using unboosted elvitegravir. Except where indicated in Table 2, the dose of boosted elvitegravir or co-administered medicinal product was the same when administered alone or in combination. The pharmacokinetic parameters of the protease inhibitors presented in Table 2 were assessed in the presence of ritonavir.

Although there may be no actual or predicted interactions between a medicinal product and elvitegravir, there may be interactions between a medicinal product and ritonavir and/or the protease

inhibitor co-administered with elvitegravir. The prescriber should always refer to the Summary of Product Characteristics for ritonavir, or the protease inhibitor.

Table 2: Interactions between elvitegravir and other medicinal products

 

Medicinal product by

 

Effects on drug levels

Recommendation concerning

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegravir

 

 

ANTIRETROVIRALS

 

 

 

 

 

 

 

 

 

HIV protease inhibitors

 

 

 

 

 

 

 

 

 

Atazanavir (300 mg once daily)

Atazanavir/Ritonavir has been

When used in combination with

 

 

Elvitegravir (200 mg once daily)

shown to significantly increase

atazanavir, the dose of Vitekta

 

 

Ritonavir (100 mg once daily)

the plasma concentrations of

should be 85 mg once daily.

 

 

 

 

elvitegravir.

 

 

When used in combination w th

 

 

 

 

Elvitegravir:

 

 

Vitekta, the recommended dose of

 

 

 

 

 

 

atazanavir is 300 mg with

 

 

 

 

AUC: ↑ 100%

 

ritonavir 100 mg once daily.

 

 

 

 

Cmax: ↑ 85%

 

 

 

 

 

 

 

 

Cmin: ↑ 188%

 

 

There are no da a available to

 

 

 

 

Atazanavir:

 

 

make dosing recommendations for

 

 

 

 

 

 

co-administr tion with other doses

 

 

 

 

AUC: ↔

 

 

of ataz n vir (see section 4.2).

 

 

 

 

Cmax: ↔

 

longer

authorised

 

 

 

 

Cmin: ↓ 35%

 

 

 

Atazanavir (300 mg once daily)

Elvitegravir:

 

 

 

 

Elvitegravir (85 mg once daily)

AUC: ↔*

 

 

 

 

Ritonavir (100 mg once daily)

Cmax: ↔*

 

 

 

 

 

 

Cmin: ↑ 38%*

 

 

 

 

 

 

Atazanavir:

no

 

 

 

 

 

AUC: ↔**

 

 

 

 

 

Cmax: ↔**

 

 

 

 

 

 

 

Cmin: ↔**

 

 

 

 

 

 

 

*

 

 

 

 

 

 

 

 

 

when ompared to

 

 

 

 

 

 

 

elvitegravir/ritonavir

 

 

 

 

 

 

 

150/100 mg once daily.

 

 

 

 

 

 

 

**when compared to

 

 

 

 

 

 

 

atazanavir/ritonavir 300/100 mg

 

 

 

 

 

 

once daily.

 

 

 

 

 

 

Darunavir (600 mg twice daily)

Elvitegravir:

 

 

When used in combination with

 

 

Elvitegravir (125 mg once daily)

AUC: ↔

 

 

darunavir, the dose of Vitekta

 

 

 

product

 

 

should be 150 mg once daily.

 

 

Ritonavir (100 mg twice daily)

Cmax: ↔

 

 

 

 

 

 

Cmin: ↔

 

 

There are no data available to

 

 

 

 

 

 

 

 

 

 

 

 

Darunavir:

 

 

make dosing recommendations for

 

 

 

 

AUC: ↔

 

 

co-administration with other doses

 

 

 

 

Cmax: ↔

 

 

of darunavir (see section 4.2).

 

 

 

 

Cmin: ↓ 17%

 

 

 

 

 

 

Fosamprenavir (700 mg twice

Elvitegravir:

 

 

When used in combination with

 

 

daily)

 

AUC: ↔

 

 

fosamprenavir, the dose of Vitekta

 

 

Elvitegravir (125 mg once daily)

Cmax: ↔

 

 

should be 150 mg once daily.

 

 

Ritonavir (100 mg twice daily)

Cmin: ↔

 

 

 

 

 

 

Medicinal

 

Fosamprenavir:

 

There are no data available to

 

 

 

 

 

make dosing recommendations for

 

 

 

 

AUC: ↔

 

 

co-administration with other doses

 

 

 

 

Cmax: ↔

 

 

of fosamprenavir (see section 4.2).

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

Medicinal product by

Effects on drug levels

Recommendation concerning

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegravir

 

 

Lopinavir/Ritonavir (400/100 mg

Lopinavir/Ritonavir has been

When used in combination with

 

 

twice daily)

shown to significantly increase

lopinavir/ritonavir, the dose of

 

 

Elvitegravir (125 mg once daily)

the plasma concentrations of

Vitekta should be 85 mg once

 

 

 

elvitegravir.

 

 

daily.

 

 

 

 

Elvitegravir:

 

 

There are no data available to

 

 

 

AUC: ↑ 75%

 

 

make dosing recommendations for

 

 

 

Cmax: ↑ 52%

 

 

 

authorised

 

 

 

 

 

co-administration with other doses

 

 

 

Cmin: ↑ 138%

 

 

of lopinavir/ritonavir (see

 

 

 

Lopinavir:

 

 

section 4.2).

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

Cmin: ↓ 8%

 

 

 

 

 

 

Tipranavir (500 mg twice daily)

Elvitegravir:

 

 

Due to insufficient clinical data,

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

the combination of elvi egravir

 

 

Ritonavir (200 mg twice daily)

Cmax: ↔

 

 

with tipranavir is not

 

 

 

Cmin: ↔

 

 

recommended (see section 4.2).

 

 

 

Tipranavir:

 

longer

 

 

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

Cmin: ↓ 11%

 

 

 

 

 

 

NRTIs

 

 

 

 

 

 

 

Didanosine (400 mg once daily)

Elvitegravir:

 

 

As didanosine is administered on

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

an empty stomach, didanosine

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

no

 

should be administered at least

 

 

 

Cmax: ↓ 16%

 

 

 

 

 

 

Cmin: ↔

 

 

one hour before or two hours after

 

 

 

Didanosine:

 

 

Vitekta (which is administered

 

 

 

 

 

with food). Clinical monitoring is

 

 

 

AUC: ↓ 14%

 

 

recommended.

 

 

 

 

 

 

 

 

 

Stavudine (40 mg once daily)productElvitegravir:

 

 

No dose adjustment is required

 

 

Zidovudine (300 mg twice daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with zidovudine.

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

Zidovudine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

Medicinal

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Elvitegravir (200 mg once daily)

 

 

 

 

Ritonavir (100 mg o ce daily)

Cmax: ↔

 

 

with stavudine.

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

Stavudine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

Abacavir (600 mg once daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with abacavir.

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

Abacavir:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

Medicinal product by

Effects on drug levels

Recommendation concerning

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegravir

 

 

Tenofovir disoproxil fumarate

Elvitegravir:

 

 

No dose adjustment is required

 

 

(300 mg once daily)

 

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Emtricitabine (200 mg once daily)

Cmax: ↔

 

 

with tenofovir disoproxil fumarate

 

 

Elvitegravir (50 mg once daily)

Cmin: ↔

 

 

or with emtricitabine.

 

 

Ritonavir (100 mg once daily)

Tenofovir:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

Emtricitabine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

NNRTIs

 

 

 

 

 

 

 

 

Efavirenz

 

Interaction not studied with

Co-administration is not

 

 

 

 

elvitegravir.

 

 

recommended (see sec ion 4.4).

 

 

 

 

Co-administration of efavirenz

 

authorised

 

 

 

 

and elvitegravir is expected to

 

 

 

 

 

decrease elvitegravir plasma

 

 

 

 

 

 

 

 

 

 

 

concentrations which may result

 

 

 

 

 

 

in loss of therapeutic effect and

 

 

 

 

 

 

possible development of

 

 

 

 

 

 

resistance.

 

 

 

 

 

 

Etravirine (200 mg twice daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with etravirine.

 

 

 

 

Cmin: ↔

no

longer

 

 

 

 

 

 

 

 

 

 

 

 

Etravirine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

Nevirapine

 

Interaction not studied with

Co-administration is not

 

 

 

 

elvitegravir.

 

 

recommended (see section 4.4).

 

 

 

 

Co-administration of nevirapine

 

 

 

 

 

 

and elvitegravir is expected to

 

 

 

 

 

 

decrease elvitegravir plasma

 

 

 

 

 

productconcentrations which may result

 

 

 

 

 

 

in loss of therapeutic effect and

 

 

 

 

 

 

possible development of

 

 

 

 

 

 

resistance.

 

 

 

 

 

 

Rilp v r ne

 

Interaction not studied with

Co-administration of elvitegravir

 

 

 

 

elvitegravir.

 

 

and rilpivirine is not expected to

 

 

 

 

 

 

 

change elvitegravir plasma

 

 

 

 

 

 

 

concentrations, therefore no dose

 

 

 

 

 

 

 

adjustment of Vitekta is required.

 

 

CCR5 antagonists

 

 

 

 

 

 

 

 

araviroc (150 mg twice daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Medicinal

 

Cmax: ↔

 

 

with maraviroc.

 

 

Ritonavir (100 mg once daily)

 

 

 

 

 

 

Cmin: ↔

 

 

§Due to inhibition of CYP3A by

 

 

 

 

Maraviroc:§

 

 

 

 

 

 

 

 

ritonavir, maraviroc exposure is

 

 

 

 

AUC: ↑ 186%

 

significantly increased.

 

 

 

 

Cmax: ↑ 115%

 

 

 

 

 

 

 

 

Cmin: ↑ 323%

 

 

 

 

 

Interaction not studied with elvitegravir.
Elvitegravir (simultaneous antacid administration): AUC: ↓ 45%
Cmax: ↓ 47%
Cmin: ↓ 41%
Elvitegravir (antacid suspension given ± 4 hours from elvitegravir administration): AUC: ↔
Cmax: ↔
Cmin: ↔

Medicinal product by

Effects on drug levels

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with

 

Cmax, Cmin

ritonavir-boosted elvitegravir

ANTACIDS

Magnesium/aluminum-containing antacid suspension (20 mL single dose)

Elvitegravir (50 mg once daily) Ritonavir (100 mg once daily)

FOOD SUPPLEMENTS

Multivitamin supplements

NARCOTIC ANALGESICS

 

 

Methadone (80-120 mg once daily)

Elvitegravir:

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

 

 

Cmin: ↔

no

 

 

Cmin: ↔

 

 

Methadone:

 

 

 

AUC: ↔

 

 

 

Cmax: ↔

 

 

productCmin: ↑ 66%

 

Buprenorphine/Naloxone (16/4 mg

Elvitegravir:

 

to 24/6 mg daily)

 

AUC: ↔

 

Elvitegravir (150 mg once daily)

Cmax: ↔

 

Cobicistat (150 mg once daily)

Cmin: ↔

 

 

 

Buprenorphine:

 

 

AUC: ↑ 35%

 

Medicinal

 

Cmax: ↑ 12%

 

 

Naloxone:

 

 

 

 

 

 

AUC: ↓ 28%

 

ANTI-INFECTIVES

 

Cmax: ↓ 28%

 

 

 

 

Antifungals

 

 

 

K toconazole (200 mg twice daily)

Elvitegravir:

 

Elvit gravir (150 mg once daily)

AUC: ↑ 48%

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

 

Cmin: ↑ 67%

 

 

 

↑ Ketoconazole§

 

 

 

 

 

Elvitegravir plasma concentrations

 

are lower with antacids due to

 

local complexation in the

 

gastrointestinal tract and not to

 

changes in gastric pH. It is

 

recommended to separate Vitekta

 

 

authorised

 

and antacid administration by at

 

least 4 hours.

 

As the effect of ca ionic

 

complexation of elvi egravir

 

cannot be excl ded when

 

co-administered with multivitamin

 

supplements, it is recommended to

longer

 

 

sepa ate Vitekta and multivitamin

 

suppl m nts dosing by at least

 

4 hours.

 

 

No dose adjustment is required

 

when Vitekta is co-administered

 

with methadone.

 

No dose adjustment is required

 

when Vitekta is co-administered

 

with buprenorphine/naloxone.

 

 

 

No dose adjustment is required when Vitekta is co-administered with ketoconazole.

§Due to inhibition of CYP3A by ritonavir, ketoconazole exposure is increased.

 

Medicinal product by

Effects on drug levels

Recommendation concerning

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegravir

 

 

HCV protease inhibitors

 

 

 

 

 

 

 

 

Telaprevir (750 mg three times

Telaprevir:

 

 

 

No dose adjustment is required

 

 

daily)/

 

AUC: ↔

 

 

 

when Vitekta is co-administered

 

 

Elvitegravir (85 mg once daily)

Cmax: ↔

 

 

 

with ritonavir-boosted atazanavir

 

 

Atazanavir (300 mg once daily)

Cmin: ↔

 

 

 

plus telaprevir.

 

 

Ritonavir (100 mg once daily)

Elvitegravir:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

 

Cmin: ↑ 40%*

 

 

 

 

 

 

 

 

 

*Compared to

 

 

 

 

 

 

 

 

atazanavir/ritonavir 300/100 mg

 

 

 

 

 

 

plus elvitegravir 85 mg once

 

 

 

 

 

 

daily.

 

 

 

 

 

 

 

Antimycobacterials

 

 

 

 

 

 

 

 

 

Rifabutin (150 mg once every

Elvitegravir:

 

 

 

Co-administration of Vitekta and

 

 

other day)

 

AUC: ↔*

 

 

 

rifabutin is not recommended. If

 

 

Elvitegravir (300 mg once daily)

Cmax: ↔*

 

 

 

the combin tion is needed, the

 

 

Ritonavir (100 mg once daily)

Cmin: ↔*

 

 

 

recommended dose of rifabutin is

 

 

 

 

 

 

 

 

 

authorised

 

 

 

 

Rifabutin:

 

 

 

150 mg 3 times per week on set

 

 

 

 

 

 

 

days (for example Monday-

 

 

 

 

AUC: ↔**

 

 

 

Wednesday-Friday).

 

 

 

 

Cmax: ↔**

 

 

 

 

 

 

 

 

 

Cmin: ↔**

 

 

 

No dose adjustment of Vitekta is

 

 

 

 

 

 

 

 

required when co-administered

 

 

 

 

 

 

 

 

with reduced dose of rifabutin.

 

 

 

 

 

 

 

longer

 

 

 

 

 

 

 

 

 

Further dose reduction of rifabutin

 

 

 

 

 

 

 

 

has not been studied. It should be

 

 

 

 

25-O-desace yl-rifabutin:§

kept in mind that a twice weekly

 

 

 

 

 

 

**

 

dose of 150 mg may not provide

 

 

 

 

 

no

 

 

 

 

 

AUC: ↑ 851%

 

an optimal exposure to rifabutin

 

 

 

 

Cmax: ↑ 440%**

 

 

 

 

 

Cmin: ↑ 1,836%**

 

thus leading to a risk of rifamycin

 

 

 

 

*when compared to

 

resistance and a treatment failure.

 

 

 

 

 

§Due to inhibition of CYP3A by

 

 

 

 

elvitegravir/ritonavir

 

 

 

 

 

300/100 mg once daily.

 

ritonavir, 25-O-desacetyl-rifabutin

 

 

 

 

**when compared to rifabutin

exposure is increased.

 

 

 

 

 

 

 

 

 

product

 

 

 

 

 

 

 

 

 

300 mg once daily.

 

 

 

 

 

 

 

Total antimycobacterial activity

 

 

 

 

 

 

was increased by 50%.

 

 

 

 

 

ANTICOAGULANTS

 

 

 

 

 

 

 

 

 

Warfar n

 

Interaction not studied with

It is recommended that the

 

 

Medicinal

 

elvitegravir.

 

 

 

international normalised ratio

 

 

 

Concentrations of warfarin may

(INR) be monitored upon

 

 

 

co-administration of Vitekta. INR

 

 

 

be affected upon

 

should continue to be monitored

 

 

 

co-administration with

 

during the first weeks following

 

 

 

elvitegravir.

 

 

 

cessation of treatment with

 

 

 

 

 

 

 

 

Vitekta.

 

 

 

H2-RECEPTOR ANTAGONISTS

 

 

 

 

 

 

 

 

Famotidine (40 mg once daily)

Elvitegravir:

 

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

 

when Vitekta is co-administered

 

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

 

 

with famotidine.

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

Medicinal product by

Effects on drug levels

Recommendation concerning

 

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegravir

 

 

HMG-CoA REDUCTASE INHIBITORS

 

 

 

 

 

 

Rosuvastatin (10 mg single dose)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

 

with rosuvastatin.

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

 

Rosuvastatin:

 

 

 

authorised

 

 

 

 

 

AUC: ↑ 38%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cmax: ↑ 89%

 

 

 

 

 

 

 

 

 

Cmin: ↑ 43%

 

 

 

 

 

 

Atorvastatin

 

Interaction not studied with

No dose adjustment is required

 

 

Fluvastatin

 

elvitegravir.

 

 

when Vitekta is co-administe ed

 

 

Pitavastatin

 

Plasma concentrations of OATP

with atorvastatin, fluvastatin,

 

 

Pravastatin

 

pitavastatin or pravastatin.

 

 

 

 

 

substrates are not expected to

 

 

 

 

 

 

 

change upon co-administration

 

 

 

 

 

 

 

of elvitegravir.

 

 

 

 

 

 

 

 

Plasma concentrations of

 

 

 

 

 

 

 

 

 

longer

 

 

 

 

 

 

elvitegravir are not expected to

 

 

 

 

 

 

 

change upon co-administration

 

 

 

 

 

 

 

of OATP substrates/inhibitors.

 

 

 

 

ORAL CONTRACEPTIVES

 

 

 

 

 

 

 

Norgestimate (0.180/0.215 mg

Norgestimate:

 

Caution should be exercised when

 

 

once daily)

 

AUC: ↑ 126%

 

co-administering Vitekta and a

 

 

Ethinylestradiol (0.025 mg once

Cmax: ↑ 108%

 

 

hormonal contraceptive. The

 

 

daily)

 

Cmin: ↑ 167%

 

 

hormonal contraceptive should

 

 

Elvitegravir (150 mg once daily)

 

 

 

contain at least 30 µg

 

 

Cobicistat (150 mg once daily)1

Ethinylestradi l:

 

ethinylestradiol and contain

 

 

 

 

 

AUC: ↓ 25%

no

 

norgestimate as the progestagen or

 

 

 

 

 

Cmax: ↔

 

patients should use an alternative

 

 

 

 

product

 

progestagens other than

 

 

 

 

 

Cmin: ↓ 44%

 

reliable method of contraception

 

 

 

 

 

Elvitegravir:

 

 

(see sections 4.4 and 4.6).

 

 

 

 

 

AUC: ↔

 

 

The long-term effects of

 

 

 

 

 

Cmax: ↔

 

 

substantial increases in

 

 

 

 

 

Cmin: ↔

 

 

progesterone exposure are

 

 

 

 

 

 

 

 

unknown. Co-administration of

 

 

 

 

 

 

 

 

elvitegravir with oral

 

 

Medicinal

 

 

 

 

contraceptives containing

 

 

 

 

 

 

norgestimate has not been studied

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

and therefore should be avoided.

 

 

PROTON PUMP INHIBITORS

 

 

 

 

 

 

 

Omeprazole (40 mg once daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elv tegrav r (50 mg once daily

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with omeprazole.

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

This study was conducted using the fixed-dose combination tablet elvitegravir/cobicistat/emtricitabine/tenofovir

 

 

 

 

disoproxil.

 

 

 

 

 

 

 

 

4.6 Fertility, pregnancy and lactation

 

 

 

 

 

Women of childbearing potential / contraception in males and females

The use of Vitekta must be accompanied by the use of effective contraception (see sections 4.4 and 4.5).

Pregnancy

There are no or limited clinical data with elvitegravir in pregnant women.

No studies on the effects of elvitegravir on the ability to

Animal studies do not indicate direct or indirect harmful effects of elvitegravir with respect to reproductive toxicity. However, the maximum exposures evaluated in the rabbit were not in excess of those achieved therapeutically (see section 5.3).

Vitekta should not be used during pregnancy unless the clinical condition of the woman requires treatment with elvitegravir.

Breast-feeding

authorised

It is unknown whether elvitegravir/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of elvitegravir in milk. A risk to the newborns/infants cannot be excluded. Therefore, Vitekta should not be used during breast- feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV infected w men do not breast-feed their infants under any circumstances.

Fertility

No human data on the effect of elvitegravir on fertility are available. Anim l st dies do not indicate harmful effects of elvitegravir on fertility.

4.7 Effects on ability to drive and use machines

drive and use machines have been performed.

4.8 Undesirable effects

longer

Summary of the safety profile

 

Assessment of adverse reactions is based on data fr

m a controlled clinical study (GS-US-183-0145)

in which 712 HIV-1 infected, antiretroviral treatme

t-experienced adults received elvitegravir

product

 

(n = 354) or raltegravir (n = 358) each admi is ered with a background regimen consisting of a fully

active ritonavir-boosted protease inhibitor and noo her antiretroviral agents. Of these 712 patients, 543

(269 elvitegravir and 274 raltegravir) and 439 (224 elvitegravir and 215 raltegravir) received at least

48 and 96 weeks of treatment, respectively.

 

The most frequently reported a verse reactions to elvitegravir were diarrhoea (7.1%) and nausea

(4.0%) (see Table 3).

 

Tabulated summary of adverse reactions

 

Medicinal

 

Adverse reactions to e vitegravir from clinical study experience are listed in Table 3 below, by body system organ cl ss nd frequency. Within each frequency grouping, undesirable effects are presented in order of decre sing seriousness. Frequencies are defined as common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1,000 to < 1/100).

Nervous system disorders:

Table 3: Tabulated summary of adverse reactions to elvitegravir based on experience for 96 weeks from clinical study GS-US-183-0145

Frequency

Adverse reaction

Psychiatric disorders:

Uncommon

suicidal ideation and suicide attempt (in patients with a pre-existing history of

depression or psychiatric illness), depression, insomnia

 

 

 

Common

headache

 

 

 

Uncommon

dizziness, paraesthesia, somnolence, dysgeusia

 

 

Gastrointestinal disorders:

 

 

 

Common

abdominal pain, diarrhoea, vomiting, nausea

 

 

Uncommon

dyspepsia, abdominal distension, flatulence

 

 

Skin and subcutaneous

tissue disorders:

 

 

 

Common

rash

 

 

 

General disorders and administration site conditions:

 

 

 

Common

fatigue

 

 

 

Description of selected adverse reactions

 

authorised

Metabolic parameters

 

Weight and levels of blood lipids and glucose may increase during antir troviral therapy (see

section 4.4).

 

longer

 

 

 

 

 

 

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) have also been rep rted; however, the reported time to onset is

more variable and these events can occur ma y m ths after initiation of treatment (see section 4.4).

Osteonecrosis

product

no

Cases of osteonecrosis have been reported, par icularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown

(see section 4.4).

 

 

 

Diarrhoea

 

 

 

In study GS-US-183-0145, dia

h ea was reported as an adverse reaction in 7.1% of subjects in the

elvitegravir group and in 5.3% of subjects in the raltegravir group. In these subjects, diarrhoea was

mild to moderate in severity and did not result in discontinuation of study drug.

Medicinal

 

 

 

Paediatric popul tion

No data are available for children below 18 years of age. Vitekta is not recommended in this populat on (see section 4.2).

Reporting of suspected adverse reactions

R porting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with elvitegravir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

There is no specific antidote for overdose with elvitegravir. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

5.

PHARMACOLOGICAL PROPERTIES

 

5.1

Pharmacodynamic properties

 

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX11.

Mechanism of action and pharmacodynamic effects

authorised

 

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encod d enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and p opagat on of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Antiviral activity in vitro

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 50%

elvitegravir when combined with antiretroviral drugs from the nucl os(t)ide reverse transcriptase

inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), integrase strand transfer inhibitor, fusion inhibitor, or CCR5 co-receptor antagonist classes showed no antagonism.

effective concentration (EC50) values were in the range of 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, longerB, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM). The in vit o antiviral activity of

Elvitegravir did not show inhibition of replicatinon f HBV or HCV in vitro.

Resistance

In cell culture

HIV-1 isolates with reducedproductsusceptibili y o elvitegravir have been selected in cell culture. Phenotypic resistance to elvitegravir was most commonly associated with the primary integrase substitutions T66I, E92Q and Q148R. Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K.

Cross resistance

Elvitegravir-resistant vi uses show varying degrees of cross-resistance to the integrase strand transfer

inhibitor raltegravir de ending on the type and number of substitutions. Viruses expressing the MedicinalT66I/A substitutions maintain susceptibility to raltegravir, while most other patterns of

elvitegravir-associ ted substitutions are associated with reduced susceptibility to raltegravir. With the exception of Y143C/R/H, HIV-1 with the primary raltegravir-associated substitutions T66K, Q148H/K/R, or N155H in integrase is associated with reduced susceptibility to elvitegravir.

In treatment-experienced patients

In an analysis of HIV-1 isolates from treatment-failure subjects in study GS-US-183-0145 through w k 96, the development of one or more primary elvitegravir resistance-associated substitutions was obs rved in 23 of the 86 subjects with evaluable genotypic data from paired baseline and elvitegravir treatment-failure isolates (23/351 elvitegravir-treated subjects, 6.6%). Similar rates of raltegravir resistance development occurred in the HIV-1 from subjects treated with raltegravir (26/351 raltegravir-treated subjects, 7.4%). The most common substitutions that emerged in HIV-1 isolates

from elvitegravir-treated subjects were T66I/A (n = 8), E92Q/G (n = 7), T97A (n = 4), S147G (n = 4), Q148R (n = 4), and N155H (n = 5) in integrase. In phenotypic analyses of HIV-1 isolates with resistance substitutions from elvitegravir-treated subjects, 14/20 (70%) had reduced susceptibility to elvitegravir and 12/20 (60%) had reduced susceptibility to raltegravir.

Clinical experience

In treatment-experienced HIV-1 infected patients

The efficacy of elvitegravir is primarily based on the analyses through 96 weeks from one randomised, double-blind, active-controlled study, study GS-US-183-0145, in treatment-experienced,

HIV-1 infected patients (n = 702).

In study GS-US-183-0145, patients were randomised in a 1:1 ratio to receive either elvitegravir

(150 mg or 85 mg) once daily or raltegravir 400 mg twice daily, each administered with a background regimen (BR) containing a fully-active ritonavir-boosted protease inhibitor (either atazanavir, darunavir, fosamprenavir, lopinavir or tipranavir) and a second agent. The BR was selected by the investigator based on genotypic/phenotypic resistance testing and prior antiretroviral treatment history. Randomisation was stratified by screening HIV-1 RNA level (≤ 100,000 copies/mL or

> 100,000 copies/mL) and the class of the second agent (NRTI or other classes). Virologic re pon e rate was evaluated in both treatment arms. Virologic response was defined as achieving an undetectable viral load (HIV-1 RNA < 50 copies/mL).

Baseline characteristics and treatment outcomes through 96 weeks for study GS-US-183-0145 are presented in Tables 4 and 5 respectively.

 

Table 4: Demographic and baseline disease characteristics of antiretrovir

l treatment-

 

experienced HIV-1 infected adult subjects in study GS-US-183-0145

authorised

 

 

 

 

 

 

 

 

 

 

Elvitegravir + background

Raltegravir + background

 

 

 

 

 

regimen

 

 

 

regimen

 

 

 

 

n = 351

 

 

 

n = 351

 

Demographic characteristics

 

 

 

 

 

 

 

 

Median age, years (min-max)

 

longer

 

 

 

 

 

 

(20-78)

 

(19-74)

 

 

Sex

 

 

 

 

 

 

 

 

 

Male

 

 

83.2%

 

 

 

80.9%

 

 

Female

 

 

16.8%

 

 

 

19.1%

 

 

 

 

 

no

 

 

 

 

 

 

Ethnicity

 

 

 

 

 

 

 

 

 

White

 

 

60.1%

 

 

 

64.4%

 

 

Black/African American

 

35.6%

 

 

 

32.2%

 

 

Asian

 

 

2.6%

 

 

 

1.4%

 

 

Other

 

 

1.7%

 

 

 

2.0%

 

 

Baseline disease characte istics

 

 

 

 

 

 

 

 

Median baseline plasma

 

4.35

 

 

 

4.42

 

 

HIV-1 RNA (range)

product

(1.69-6.63)

 

 

(1.69-6.10)

 

 

log10 copies/mL

 

 

 

 

 

 

 

Percentage of subjects with

 

25.6

 

 

 

25.6

 

 

viral load > 100,000 copies/mL

 

 

 

 

 

 

 

 

Med an basel ne CD4+ cell

 

227.0

 

 

 

215.0

 

 

count (range), cells/mm3

(2.0-1,374.0)

 

 

(1.0-1,497.0)

 

 

Percentage of subjects with

 

44.4

 

 

 

44.9

 

 

CD4+ cell counts

 

 

 

 

 

 

 

 

 

≤ 200 cells/mm3

 

 

 

 

 

 

 

 

 

Baseline genotypic sensitivity

 

 

 

 

 

 

 

 

scorea

 

 

 

 

 

 

 

 

Medicinal0

 

 

1%

 

 

 

< 1%

 

 

 

14%

 

 

 

15%

 

 

 

81%

 

 

 

83%

 

 

 

3%

 

 

 

2%

 

aGenotypic sensitivity scores are calculated by summing up drug susceptibility values (1 = sensitive; 0 = reduced susceptibility) on all drugs in the baseline background regimen.

Table 5: Virologic outcome of randomised treatment of study GS-US-183-0145 at week 48 and week 96 (snapshot analysis)a

 

Week 48

Week 96

 

 

Elvitegravir

 

Raltegravir

Elvitegravir

Raltegravir

 

 

+ background

 

+ background

+ background

+ background

 

 

regimen

 

regimen

regimen

regimen

 

 

n = 351

 

n = 351

n = 351

n = 351

 

Virologic success

60%

 

58%

52%

53%

 

HIV-1 RNA

 

 

 

 

 

 

< 50 copies/mL

 

 

 

 

 

 

Treatment difference

2.2% (95% CI =

-5.0%, 9.3%)

-0.5% (95% CI = -7.9%, 6.8%)

 

Virologic failureb

33%

 

32%

36%

31%

 

No virologic data at

7%

 

11%

12%

16%

 

week 48 or week 96

 

 

 

 

 

 

window

 

 

 

 

 

 

Discontinued study drug

2%

 

5%

3%

7%

 

due to AE or deathc

 

 

 

 

 

 

Discontinued study drug

4%

 

5%

8%

9%

 

due to other reasons and

 

 

 

authorised

 

last available

 

 

 

 

HIV-1 RNA

 

 

 

 

 

 

< 50 copies/mLd

 

 

 

 

 

 

Missing data during

1%

 

1%

1%

1%

 

window but on study

 

 

 

 

 

 

drug

 

 

 

 

 

 

a Week 48 window is between day 309 and 364 (inclusive), week 96 window is between day 645 and 700 (inclusive).

b Includes subjects who had ≥ 50 copies/mL in the week 48 r weeklonger96 window, subjects who discontinued early due to

lack or loss of efficacy, subjects who had a viral load ≥ 50 c pies/mL at time of change in background regimen, subjects

who discontinued for reasons other than an adverse eve t (AE), death or lack or loss of efficacy and at the time of

discontinuation had a viral load of ≥ 50 copies/mL.

no

 

 

 

cIncludes patients who discontinued due to an AE or death at any time point from day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

dIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.

Elvitegravir was non-infeproducti in achieving HIV-1 RNA < 50 copies/mL when compared to raltegravir. Among subjects with a genotypic sensitivity score of ≤ 1, 76% and 69% had HIV-1 RNA

< 50 copies/mL at week 48 in the elvitegravir and raltegravir treatment arms, respectively. Among Medicinalsubjects with genotypic sensitivity score > 1, 57% and 56% had HIV-1 RNA < 50 copies/mL at

week 48 in the elvitegravir and raltegravir treatment arms, respectively.

In study GS-US-183-0145, the mean increase from baseline in CD4+ cell count at week 96 was

205 ells/mm3 in the elvitegravir-treated patients and 198 cells/mm3 in the raltegravir-treated patients.

In stu y GS-US-183-0145, subgroup analyses by co-administered protease inhibitor showed similar rat s of virologic success for elvitegravir and raltegravir within each protease inhibitor subgroup at weeks 48 and 96 (HIV-1 RNA < 50 copies/mL) (Table 6).

Table 6: Virologic success by co-administered protease inhibitor in study GS-US-183-0145 at week 48 and week 96 (snapshot analysis)

 

 

 

Elvitegravir versus

 

 

 

raltegravir

HIV-1 RNA

Elvitegravir

Raltegravir

Difference in percentages

 

< 50 copies/mL, n/N (%)

(N = 351)

(N = 351)

(95% CI)a

Virologic success at

 

 

 

 

 

week 48

 

 

 

 

 

Tipranavir/ritonavir

3/6 (50.0%)

3/7 (42.9%)

7.1%authorised(-47.1% to 61.4%)

 

Darunavir/ritonavir

126/202 (62.4%)

122/207 (58.9%)

3.4%

(-6.0% to 12.9%)

Lopinavir/ritonavir

39/68 (57.4%)

37/68 (54.4%)

2.9%

(-13.7% to 19.6%)

 

Atazanavir/ritonavir

34/61 (55.7%)

28/51 (54.9%)

0.8%

(-17.7% to 19.3%)

 

Fosamprenavir/ritonavir

8/14 (57.1%)

10/18 (55.6%)

1.6%

(-33.0% to 36.2%)

 

Tipranavir/ritonavir

3/6 (50.0%)

5/7 (71.4%)

-21.4% (-73.6% to 30.7%)

 

Virologic success at

 

 

 

 

 

week 96

 

 

 

 

 

Darunavir/ritonavir

105/202 (52.0%)

112/207 (54.1%)

-2.1% (-11.8% to 7.5%)

 

Lopinavir/ritonavir

36/68 (52.9%)

37/68 (54.4%)

-1.5% (-18.2% to 15.3%)

 

Atazanavir/ritonavir

33/61 (54.1%)

23/51 (45.1%)

9.0%

(-9.5% to 27.5%)

 

Fosamprenavir/ritonavir

7/14 (50.0%)

11/18 (61.1%)

-11.1% (-45.7% to 23.4%)

 

 

 

longer

 

 

 

a The difference in proportions and its 95% CIs between randomised treatment groups is based on normal approximation.

Although limited by the small number of female subjects in study GS-US-183-0145, subgroup analysis by gender showed that the rates of virologic success in female subjects at weeks 48 and 96 (HIV-1 RNA < 50 copies/mL) were numerically lower in the elvitegravir treatment arm than in the raltegravir treatment arm. Virologic success rates at week 48 f r elvitegravir and raltegravir were 47.5% (28/59) and 62.7% (42/67) (difference: -no12.3% [95% CI: -30.1% to 5.5%]), respectively, for female subjects, and 62.3% (182/292) and 56.3% (160/284) (difference: 5.3% [95% CI: -2.5% to 13.2%]), respectively, for male subjects. Virologic success rates at week 96 for elvitegravir and

[95% CI: -6.5% to 9.6%]), respectively, for male subjects.

raltegravir were 39.0%product(23/59) and 52.2% (35/67) (difference: -8.4% [95% CI: -26.1% to 9.2%]), respectively, for female subjects, and 55.1% (161/292) and 53.2% (151/284) (difference: 1.5%

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with elvitegravir in one or mo e subsets of the paediatric population in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

Medicinal5.2 Pharm cokinetic properties

Absorpt on

Following oral administration of ritonavir-boosted elvitegravir with food in HIV-1 infected subjects, elv tegrav r peak plasma concentrations were observed 4 hours post-dose. The steady-state mean Cmax,

AUCtau, and Ctrough (mean ± SD) following multiple doses of elvitegravir plus a ritonavir-boosted prot ase inhibitor (150 mg elvitegravir with darunavir or fosamprenavir; 85 mg elvitegravir with

atazanavir or lopinavir) in HIV-1 infected subjects were 1.4 ± 0.39 μg/mL, 18 ± 6.8 μg•h/mL, and 0.38 ± 0.22 μg/mL for elvitegravir, respectively. The absolute oral bioavailability has not been determined.

Relative to fasting conditions, the administration of boosted elvitegravir as the fixed-dose combination 150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/245 mg tenofovir disoproxil with a light meal (approximately 373 kcal, 20% fat) or high-fat meal (approximately 800 kcal, 50% fat) resulted in increased exposures of elvitegravir. The Cmax and AUCtau of elvitegravir increased 22% and 36% with a light meal, while increasing 56% and 91% with a high-fat meal, respectively.

Distribution

Elvitegravir is 98-99% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1.0 ng/mL to 1.6 µg/mL. The mean plasma to blood drug concentration ratio is 1.37.

Biotransformation

Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation via UGT1A1/3 enzymes (minor route).

Administration of once-daily ritonavir (20-200 mg) results in an increased elvitegravir exposure following repeat once-daily administration, with elvitegravir exposure reaching a plateau with approximately 100 mg of ritonavir. Further increases in ritonavir dose do not result in further increases in elvitegravir exposure. Vitekta is indicated for use only when co -administered w th ritonavir as a boosting agent.

Ritonavir inhibits CYP3A, thereby substantially increasing the plasma concentrationsauthorisedof elvitegravir.

Mean steady-state exposure (AUCtau) of unboosted elvitegravir is ~ 20% lower af er mul iple dosing versus a single dose, indicating modest autoinduction of its metabolism. Upon boos ing with ritonavir (100 mg), net inhibition of elvitegravir metabolism is observed with signific ntly increased systemic exposures (20-fold higher AUC), high trough concentrations, and longer medi n elimination half-life (9.5 versus 3.5 hours).

Following oral administration of a single dose of ritonavirlonger-boosted [14C] lvitegravir, elvitegravir was

the predominant species in plasma, representing approximately 94% and 61% of the circulating radioactivity at 32 and 48 hours, respectively. Metabolites produced by aromatic and aliphatic

hydroxylation or glucuronidation are present in very low levels a d do not contribute to the overall antiviral activity of elvitegravir.

Following oral administration of ritonavir-boostedno[14C]elvitegravir, 94.8% of the dose was recovered

Elimination

in faeces, consistent with the hepatobiliary elimi ation of elvitegravir; 6.7% of the administered dose was recovered in urine productas metabolites. The median terminal plasma half-life of ritonavir-boosted elvitegravir is approximately 8.7 to 13.7 hours.

Linearity/non-linearity

Elvitegravir plasma exposures are non-linear and less than dose-proportional, likely due to solubility- limited absorption.

Elderly

MedicinalPharmacokinetics of e vitegravir have not been fully evaluated in the elderly (over 65 years of age). Gender

No clin ally relevant pharmacokinetic differences due to gender have been identified for boosted elv tegrav r.

Ethnicity

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for boosted lvit gravir.

Paediatric population

The pharmacokinetics of elvitegravir in paediatric subjects have not been established.

Renal impairment

A study of the pharmacokinetics of boosted elvitegravir was performed in non HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with severe

renal impairment and healthy subjects. No dose adjustment of Vitekta is required for patients with renal impairment.

Hepatic impairment

Elvitegravir is primarily metabolised and eliminated by the liver. A study of the pharmacokinetics of boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dose adjustment of

Vitekta is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravirauthorisedhas not been studied.

Hepatitis B and/or hepatitis C virus co-infection

Limited data from population pharmacokinetic analysis (n = 56) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of boosted elvitegravir.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional st dies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction

and development. The maximum doses of elvitegravir tested in the development toxicity studies in

rats and rabbits corresponded to exposures that are approximately 29-fold nd 0.2-fold the human

therapeutic exposure, respectively.

longer

 

Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in an

in vivo rat micronucleus assay at doses up to 2,000 mg/kg. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.

Elvitegravir did not show any carcinogenic potentialnoin l ng-term oral carcinogenicity studies in mice and rats.

Tablet core product

MedicinalCroscarmellose sodium

The active substance elvitegravir is persis ent in the environment.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydroxypropyl cellulose

Lactose mo ohydr te

Magnes um stearate

Micro rystalline cellulose

So um lauryl sulfate

Film-coating

Indigo carmine aluminium lake (E132) acrogol 3350 (E1521)

Polyvinyl alcohol (partially hydrolysed) (E1203)

Talc (E553B)

Titanium dioxide (E171)

Iron oxide yellow (E172)

6.2Incompatibilities

Not applicable.

Any unused medicinal product or waste material should be disposed of in requirements.
Pack size: 1 bottle of 30 film-coated tablets.
6.3 Shelf life
4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant closure containing 30 film-coated tablets.

authorised

6.6Special precautions for disposal

ccord nce with local

7.

MARKETING AUTHORISATION HOLDER

longer

Gilead Sciences International Limited

 

Cambridge

 

CB21 6GT

 

United Kingdom

 

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

 

no

 

EU/1/13/883/001

9.DATE OF FIRSTOF THE AUTHORISATIONAUTHORISATION/RENEWAL

 

product

Date of first authorisation: 13 November 2013

Medicinal

 

10. DATE OF REVISION OF THE TEXT

Deta led nformation on this medicinal product is available on the website of the European Medicines Agen y http://www.ema.europa.eu.

Film-coated tablet (tablet).
For the full list of excipients, see section 6.1.
Each film-coated tablet contains 150 mg of elvitegravir.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Vitekta 150 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient with known effect: Each tablet contains 10.9 mg lactose (as monohydrate)authorised.

3. PHARMACEUTICAL FORM

Green, triangle-shaped, film-coated tablet of dimensionslonger10.9 mm x 10.5 mm, debossed with “GSI” on one side of the tablet and “150” on the other side of the tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

product

no

Vitekta co-administered with a ritonavir-boos ed protease inhibitor and with other antiretroviral

agents, is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults

who are infected with HIV-1 witho t known mutations associated with resistance to elvitegravir (see sections 4.2 and 5.1).

4.2 Posology and meth d f a ministration

Therapy should be initiated by a physician experienced in the management of HIV infection.

MedicinalPosology

Vitekta must be dministered in combination with a ritonavir-boosted protease inhibitor.

The Summary of Product Characteristics for the co-administered ritonavir-boosted protease inhibitor should be onsulted.

The recommended dose of Vitekta is one 85 mg tablet or one 150 mg tablet taken orally once daily with food. The choice of dose of Vitekta depends on the co-administered protease inhibitor (see Table 1 and sections 4.4 and 4.5). For use of the 85 mg tablet, please refer to the Summary of Product Characteristics for Vitekta 85 mg tablets.

Vitekta should be administered once daily as follows:

-Either at the same time as a once daily ritonavir-boosted protease inhibitor

-Or with the first dose of a twice daily ritonavir-boosted protease inhibitor.

antimycobacterials: rifampicin
herbal products: St. John’s wort (Hypericum perforatum)
23

Table 1: Recommended dosing regimens

Dose of Vitekta

Dose of co-administered ritonavir-boosted protease inhibitor

 

85 mg once daily

atazanavir 300 mg and ritonavir 100 mg once daily

 

 

 

lopinavir 400 mg and ritonavir 100 mg twice daily

 

 

 

 

 

 

150 mg once daily

darunavir 600 mg and ritonavir 100 mg twice daily

 

 

 

fosamprenavir 700 mg and ritonavir 100 mg twice daily

 

 

 

 

If the patient vomits within 1 hour

of taking Vitekta another tablet should beauthorisedtaken.

 

There are no data to recommend the use of Vitekta with dosing frequencies or HIV-1 protease inhibitors other than those presented in Table 1.

Missed dose

If the patient misses a dose of Vitekta within 18 hours of the time it is usually taken, e patient should take Vitekta with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Vitekta by more than 18 hours, and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

Special populations

longer

 

Elderly

No data are available on which to make a dose recommendati n for patients over the age of 65 years (see section 5.2).

Renal impairment

 

No dose adjustment of Vitekta is required for patients with renal impairment (see section 5.2).

Hepatic impairment

no

 

hepatic impairment (Child-Pugh Class C) (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of elvitegravir in children aged 0 to less than 18 years have not yet been

No dose adjustment of productVitekta is req ired in patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). Elvitegravir has not been studied in patients with severe

established (see section 5.1). No data are available. MedicinalMethod of admi istr tion

Vitekta should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not be hewed or crushed.

4.3 Contraindications

Hyp rsensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with the following medicinal products due to the potential for loss of virologic

response and possible development of resistance (see section 4.5):

anticonvulsants: carbamazepine, phenobarbital, phenytoin

4.4 Special warnings and precautions for use

General

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

The use of Vitekta with HIV-1 protease inhibitors or dosing frequencies other than those presented in

Table 1 may result in inadequate or elevated plasma levels of elvitegravir and/or the co-administered

medicinal products.

authorised

 

Resistance

Elvitegravir-resistant viruses show cross-resistance to the integrase strand transfer inhibitor raltegravir in most cases (see section 5.1).

Elvitegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, Vitekta should be administered with a fully active ritonavir-boosted protease inhibitor and a second fully active antiretroviral agent to minimise the potential for virologic failure and the development of resistance (see section 5.1).

Co-administration of other medicinal products

longer

 

Elvitegravir is primarily metabolised by CYP3A. Co-administration of Vit kta with strong CYP3A inducers (including St. John’s wort [Hypericum perforatum], rifampicin, carbamazepine, phenobarbital and phenytoin) is contraindicated (see sections 4.3 and 4.5). Co-administration of Vitekta with moderate CYP3A inducers (including, but not limited to, efavirenz and bosentan) is not recommended (see section 4.5).

Due to the need for co-administration of Vitektanowith a ritonavir-boosted protease inhibitor, prescribers should consult the Summary of Product Characteristics of the co-administered protease

inhibitor and ritonavir for a description of co trai dicated medicinal products and other significant drug-drug interactionsproductthat may cause po en ially life-threatening adverse reactions or loss of therapeutic effect and possible development of resistance.

Atazanavir/ritonavir and lopinavir/ritonavir have been shown to significantly increase the plasma concentrations of elvitegravir (see section 4.5). When used in combination with atazanavir/ritonavir and lopinavir/ritonavir, the d se f Vitekta should be decreased from 150 mg once daily to 85 mg once daily (see section 4.2). Please efer to the Summary of Product Characteristics for Vitekta 85 mg tablets.

MedicinalCo-administration of Vitekta and related active substances: Vitekta must be used in combination with a ritonavir-boosted protease inhibitor. Vitekta should not be used with a protease inhibitor boosted by

another age t s dosing recommendations for such combinations have not been established. Boosting elvitegrav r w th an agent other than ritonavir may result in suboptimal plasma concentrations of

elv tegrav r and/or the protease inhibitor leading to loss of therapeutic effect and possible development of res stan e.

Vit kta should not be used in combination with products containing elvitegravir or pharmacokinetic boosting agents other than ritonavir.

Contraception requirements

Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 µg ethinylestradiol and containing norgestimate as the progestagen or should use an alternative reliable method of contraception (see sections 4.5 and 4.6). Co-administration of elvitegravir with oral contraceptives containing progestagens other than norgestimate have not been studied and, therefore, should be avoided.

Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency (see section 4.5).

Opportunistic infections

Patients receiving Vitekta or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Patients with HIV and hepatitis B or C virus co-infection

authorised

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV).

Liver disease

Elvitegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). No dose adjustment of Vitekta is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B) (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antir trovi al therapy (CART) and should be monitored according to standard practice. If there is evid nce of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and g uc se may occur during antiretroviral

therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in

 

longer

some cases evidence for a treatment effect, while f r weight gain there is no strong evidence relating

this to any particular treatment. For monitori g of blood lipids and glucose reference is made to

established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

no

 

Immune Reactivation Syndrome

 

retinitis, generalised and/orproductfocal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory sym toms should be evaluated and treatment instituted when necessary.

In HIV infected patients with severe imm ne deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause

serious clinical conditions,

r aggravation of symptoms. Typically, such reactions have been observed

within the first few weeks

m nths of initiation of CART. Relevant examples are cytomegalovirus

MedicinalOsteone rosis

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune react v tion; however, the reported time to onset is more variable and these events can occur many mo ths after initiation of treatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been r ported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Excipients

Vitekta contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Interactions with CYP3A inducers

Elvitegravir is primarily metabolised by CYP3A (see section 5.2). Medicinal products that are strong (causing a > 5-fold increase in substrate clearance) or moderate (causing a 2-5 fold increase in substrate clearance) inducers of CYP3A are expected to decrease plasma concentrations of elvitegravir.

Co-administration of Vitekta with medicinal products that are strong inducers of CYP3A is contraindicated as the expected decrease in plasma concentrations of elvitegravir can lead to lo of therapeutic effect and possible development of resistance to elvitegravir (see section 4.3).

Concomitant use contraindicated

authorised

 

Concomitant use not recommended

Co-administration of Vitekta with medicinal products that are moderate inducers of CYP3A (including, but not limited to, efavirenz and bosentan) is not recommended as the expec ed decrease in plasma concentrations of elvitegravir can lead to loss of therapeutic effect nd possible development of resistance to elvitegravir (see section 4.4).

Interactions requiring dose adjustment of Vitekta

longer

 

Elvitegravir undergoes oxidative metabolism by CYP3A (major rout ), and glucuronidation by UGT1A1/3 enzymes (minor route). Co-administration of Vitekta with medicinal products that are potent inhibitors of UGT1A1/3 may result in increased elvitegravir plasma concentrations and dose modifications may be required. For example, atazanavir/rit avir and lopinavir/ritonavir (potent UGT1A1/3 inhibitors) have been shown to significant y increase the plasma concentrations of elvitegravir (see Table 2). Accordingly, when used in c mbination with atazanavir/ritonavir and lopinavir/ritonavir, the dose of Vitekta should be decreased from 150 mg once daily to 85 mg once daily (see sections 4.2 and 4.4). Please refer to the Summary of Product Characteristics for Vitekta

85 mg tablets.

no

 

Other interactions

Elvitegravir is a modestproductinducer and may have the potential to induce CYP2C9 and/or inducible UGT

enzymes. As such, elvitegravir may ecrease the plasma concentration of substrates of CYP2C9 (such as warfarin) or UGT (such as ethinyl estradiol). In addition, in vitro studies have shown that elvitegravir is a weak to m dest inducer of CYP1A2, CYP2C19 and CYP3A enzymes. Elvitegravir

would also have potential to be a weak to modest inducer of CYP2B6 and CYP2C8 enzymes, as these Medicinalenzymes are regu ated in a similar manner to CYP2C9 and CYP3A. However, clinical data have

shown there are no c inically relevant changes in the exposure of methadone (which is primarily metabolised by CYP2B6 and CYP2C19) following co-administration with boosted elvitegravir versus administrat on of methadone alone (see Table 2).

Elv tegrav r is a substrate for OATP1B1 and OATP1B3, and an inhibitor of OATP1B3 in vitro. The in v vo relevance of these interactions is not clear.

Int ractions between elvitegravir and potential co-administered medicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). These interactions are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

Where interactions were studied, the effect on Vitekta was determined by comparing the pharmacokinetics of boosted elvitegravir (using either ritonavir or cobicistat as a pharmacokinetic enhancer) in the absence and presence of the co-administered medicinal product. No interactions were studied using unboosted elvitegravir. Except where indicated in Table 2, the dose of boosted elvitegravir or co-administered medicinal product was the same when administered alone or in

combination. The pharmacokinetic parameters of the protease inhibitors presented in Table 2 were assessed in the presence of ritonavir.

Although there may be no actual or predicted interactions between a medicinal product and elvitegravir, there may be interactions between a medicinal product and ritonavir and/or the protease inhibitor co-administered with elvitegravir. The prescriber should always refer to the Summary of Product Characteristics for ritonavir, or the protease inhibitor.

 

Table 2: Interactions between elvitegravir and other medicinal products

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

authorised

 

Medicinal product by

Effects on drug levels

Recommendation concerning

 

 

therapeutic areas

Mean percent change in AUC,

co-administration with

 

 

 

 

Cmax, Cmin

 

ritonavir-boosted elvitegrav r

 

 

ANTIRETROVIRALS

 

 

 

 

 

 

 

 

HIV protease inhibitors

 

 

 

 

 

 

 

 

Atazanavir (300 mg once daily)

Atazanavir/Ritonavir has been

When used in combinati n with

 

 

Elvitegravir (200 mg once daily)

shown to significantly increase

atazanavir, the dose of Vitekta

 

 

Ritonavir (100 mg once daily)

the plasma concentrations of

should be 85 mg once daily.

 

 

 

 

elvitegravir.

 

 

When used in combina ion with

 

 

 

 

Elvitegravir:

 

 

Vitekta, the recommended dose of

 

 

 

 

 

 

atazanavir is 300 mg with

 

 

 

 

AUC: ↑ 100%

 

ritonavir 100 mg once daily.

 

 

 

 

Cmax: ↑ 85%

 

 

 

 

 

 

 

 

Cmin: ↑ 188%

 

 

Th re are no data available to

 

 

 

 

Atazanavir:

 

 

make dosing recommendations for

 

 

 

 

 

 

co-administration with other doses

 

 

 

 

AUC: ↔

 

 

of atazanavir (see section 4.2).

 

 

 

 

Cmax: ↔

 

longer

 

 

 

 

 

Cmin: ↓ 35%

no

 

 

 

Atazanavir (300 mg once daily)

Elvitegravir:

 

 

 

Elvitegravir (85 mg once daily)

AUC: ↔*

 

 

 

 

 

 

Ritonavir (100 mg once daily)

Cmax: ↔*

 

 

 

 

 

 

 

 

Cmin: ↑ 38%*

 

 

 

 

 

 

 

product

 

 

 

 

 

 

 

 

Atazanavir:

 

 

 

 

 

 

 

 

AUC: ↔**

 

 

 

 

 

 

 

 

Cmax: ↔**

 

 

 

 

 

 

 

 

Cmin: ↔**

 

 

 

 

 

 

 

 

*when compared to

 

 

 

 

 

 

 

elvitegravir/ritonavir

 

 

 

 

 

Medicinal

 

150/100 mg once daily.

 

 

 

 

 

**when compared to

 

 

 

 

 

 

 

 

 

 

 

 

 

 

atazanavir/ritonavir 300/100 mg

 

 

 

 

 

 

once daily.

 

 

 

 

 

 

Darunav r (600 mg twice daily)

Elvitegravir:

 

 

When used in combination with

 

 

Elv tegrav r (125 mg once daily)

AUC: ↔

 

 

darunavir, the dose of Vitekta

 

 

Ritonavir (100 mg twice daily)

Cmax: ↔

 

 

should be 150 mg once daily.

 

 

 

 

Cmin: ↔

 

 

There are no data available to

 

 

 

 

 

 

 

 

 

 

 

Darunavir:

 

 

make dosing recommendations for

 

 

 

 

AUC: ↔

 

 

co-administration with other doses

 

 

 

 

Cmax: ↔

 

 

of darunavir (see section 4.2).

 

 

 

 

Cmin: ↓ 17%

 

 

 

 

 

 

Fosamprenavir (700 mg twice

Elvitegravir:

 

 

When used in combination with

 

 

daily)

AUC: ↔

 

 

fosamprenavir, the dose of Vitekta

 

 

Elvitegravir (125 mg once daily)

Cmax: ↔

 

 

should be 150 mg once daily.

 

 

Ritonavir (100 mg twice daily)

Cmin: ↔

 

 

There are no data available to

 

 

 

 

 

 

 

 

 

Fosamprenavir:

 

make dosing recommendations for

 

 

 

AUC: ↔

 

 

co-administration with other doses

 

 

 

Cmax: ↔

 

 

of fosamprenavir (see section 4.2).

 

 

 

Cmin: ↔

 

 

 

 

 

 

Lopinavir/Ritonavir (400/100 mg

Lopinavir/Ritonavir has been

When used in combination with

 

 

twice daily)

shown to significantly increase

 

authorised

 

 

lopinavir/ritonavir, the dose of

 

 

Elvitegravir (125 mg once daily)

the plasma concentrations of

Vitekta should be 85 mg once

 

 

 

elvitegravir.

 

 

daily.

 

 

 

 

Elvitegravir:

 

 

There are no data available to

 

 

 

AUC: ↑ 75%

 

 

make dosing recommendati ns for

 

 

 

Cmax: ↑ 52%

 

 

co-administration with ther d ses

 

 

 

Cmin: ↑ 138%

 

 

of lopinavir/ritonavir (see

 

 

 

Lopinavir:

 

 

section 4.2).

 

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

longer

 

 

 

 

Cmin: ↓ 8%

 

 

 

 

 

 

 

 

 

 

 

Tipranavir (500 mg twice daily)

Elvitegravir:

 

 

Due to insufficient clinical data,

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

the combination of elvitegravir

 

 

Ritonavir (200 mg twice daily)

Cmax: ↔

 

 

with tipranavir is not

 

 

 

Cmin: ↔

 

 

recommended (see section 4.2).

 

 

 

Tipranavir:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

Cmin: ↓ 11%

 

 

 

 

 

 

NRTIs

 

 

 

 

 

 

 

Didanosine (400 mg once daily)

Elvitegravir:

no

 

As didanosine is administered on

 

 

Ritonavir (100 mg once daily)productCmax: ↔

 

with zidovudine.

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

an empty stomach, didanosine

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

should be administered at least

 

 

 

Cmin: ↔

 

 

one hour before or two hours after

 

 

 

Di anosine:

 

 

Vitekta (which is administered

 

 

 

 

 

with food). Clinical monitoring is

 

 

 

AUC: ↓ 14%

 

 

recommended.

 

 

 

Cmax: ↓ 16%

 

 

 

 

 

 

Zidovudine (300 mg twice daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Medicinal

Cmin: ↔

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Zidovudine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

Stavu ine (40 mg once daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvit gravir (200 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with stavudine.

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

Stavudine:

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

Abacavir (600 mg once daily)

Elvitegravir:

 

 

 

No dose adjustment is required

 

 

Elvitegravir (200 mg once daily)

AUC: ↔

 

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

 

with abacavir.

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

 

Abacavir:

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

Tenofovir disoproxil fumarate

Elvitegravir:

 

 

 

No dose adjustment is required

 

 

(300 mg once daily)

 

AUC: ↔

 

 

 

when Vitekta is co-administered

 

 

Emtricitabine (200 mg once daily)

Cmax: ↔

 

 

 

with tenofovir disoproxil fumarate

 

 

Elvitegravir (50 mg once daily)

Cmin: ↔

 

 

 

or with emtricitabine.

 

 

Ritonavir (100 mg once daily)

Tenofovir:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

 

Emtricitabine:

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

NNRTIs

 

 

 

 

 

 

authorised

 

 

Efavirenz

 

Interaction not studied with

 

Co-administration is not

 

 

 

 

elvitegravir.

 

 

 

r comm nded (see section 4.4).

 

 

 

 

Co-administration of efavire

z

 

 

 

 

 

 

and elvitegravir is expected to

 

 

 

 

 

 

decrease elvitegravir p asma

 

 

 

 

 

 

 

concentrations which may result

 

 

 

 

 

 

in loss of therapeutic effect and

 

 

 

 

 

 

 

 

longer

 

 

 

 

 

possible devel pme t f

 

 

 

 

 

 

 

resistance.

 

 

 

 

 

 

 

Etravirine (200 mg twice daily)

Elvitegravir:

no

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

 

with etravirine.

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

 

Etravirine:

 

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

Nevirapine

 

Interaction not studied with

 

Co-administration is not

 

 

 

productelvitegravir.

 

 

 

recommended (see section 4.4).

 

 

 

 

Co-administration of nevirapine

 

 

 

 

 

and elvitegravir is expected to

 

 

 

 

 

decrease elvitegravir plasma

 

 

 

 

 

 

 

concentrations which may result

 

 

 

 

 

in loss of therapeutic effect and

 

 

 

 

 

possible development of

 

 

 

 

 

 

 

resistance.

 

 

 

 

 

 

 

Rilpivirine

 

Interaction not studied with

 

Co-administration of elvitegravir

 

 

Medicinal

 

elvitegravir.

 

 

 

and rilpivirine is not expected to

 

 

 

 

 

 

 

change elvitegravir plasma

 

 

 

 

 

 

 

concentrations, therefore no dose

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

adjustment of Vitekta is required.

 

 

CCR5 antagonists

 

 

 

 

 

 

 

 

Maraviroc (150 mg twice daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with maraviroc.

 

 

 

 

Cmin: ↔

 

 

§Due to inhibition of CYP3A by

 

 

 

 

Maraviroc:§

 

 

 

 

 

 

 

 

ritonavir, maraviroc exposure is

 

 

 

 

AUC: ↑ 186%

 

significantly increased.

 

 

 

 

Cmax: ↑ 115%

 

 

 

 

 

 

 

 

Cmin: ↑ 323%

 

 

 

 

 

 

ANTACIDS

 

 

 

 

 

 

 

 

Magnesium/aluminum-containing

Elvitegravir (antacid suspension

Elvitegravir plasma concentrations

 

 

antacid suspension (20 mL single

given ± 4 hours from

 

are lower with antacids due to

 

 

dose)

 

elvitegravir administration):

local complexation in the

 

 

Elvitegravir (50 mg once daily)

AUC: ↔

 

 

gastrointestinal tract and not to

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

changes in gastric pH. It is

 

 

 

 

Cmin: ↔

 

 

recommended to separate Vitekta

 

 

 

 

Elvitegravir (simultaneous

and antacid adminis ra ion by at

 

 

 

 

least 4 hours.

 

 

 

 

antacid administration):

 

 

authorised

 

 

 

 

AUC: ↓ 45%

 

 

 

 

 

 

 

Cmax: ↓ 47%

 

 

 

 

 

 

 

Cmin: ↓ 41%

 

 

 

 

 

FOOD SUPPLEMENTS

 

 

 

 

 

 

 

Multivitamin supplements

Interaction not studied with

As the ffect of cationic

 

 

 

 

elvitegravir.

 

 

complexation of elvitegravir

 

 

 

 

 

 

 

cannot be excluded when

 

 

 

 

 

 

 

co-administered with multivitamin

 

 

 

 

 

 

 

supplements, it is recommended to

 

 

 

 

 

 

 

separate Vitekta and multivitamin

 

 

 

 

 

 

 

supplements dosing by at least

 

 

 

 

 

 

longer

 

 

 

 

 

 

 

 

4 hours.

 

 

 

NARCOTIC ANALGESICS

 

 

 

 

 

 

 

Methadone (80-120 mg once daily)

Elvitegravir:

no

 

No dose adjustment is required

 

 

Elvitegravir (150 mg once daily)

AUC: ↔

 

when Vitekta is co-administered

 

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

 

with methadone.

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

 

Methadone:

 

 

 

 

 

 

 

 

AUC: ↔

 

 

 

 

 

 

 

 

Cmax: ↔

 

 

 

 

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

Buprenorphine/Na oxone (16/4 mg

Elvitegravir:

 

 

No dose adjustment is required

 

 

to 24/6 mg daily)

productAUC: ↔

 

 

when Vitekta is co-administered

 

 

Elvitegravir (150 mg once daily)

Cmax: ↔

 

 

with buprenorphine/naloxone.

 

 

Cobicistat (150 mg once daily)

Cmin: ↔

 

 

 

 

 

 

Medicinal

 

Buprenorphine:

 

 

 

 

 

 

AUC: ↑ 35%

 

 

 

 

 

 

 

Cmax: ↑ 12%

 

 

 

 

 

 

 

Cmin: ↑ 66%

 

 

 

 

 

 

 

Naloxone:

 

 

 

 

 

 

 

AUC: ↓ 28%

 

 

 

 

 

 

 

Cmax: ↓ 28%

 

 

 

 

 

ANTI-INFECTIVES

Antifungals

Ketoconazole (200 mg twice daily)

Elvitegravir:

Elvitegravir (150 mg once daily)

AUC: ↑ 48%

Ritonavir (100 mg once daily)

Cmax: ↔

 

Cmin: ↑ 67%

 

↑ Ketoconazole§

 

 

No dose adjustment is required when Vitekta is co-administered with ketoconazole.

§Due to inhibition of CYP3A by ritonavir, ketoconazole exposure is increased.

 

Antimycobacterials

 

 

 

 

 

 

 

 

 

 

authorised

 

 

Rifabutin (150 mg once every

Elvitegravir:

 

Co-administration of Vitekta and

 

other day)

 

AUC: ↔*

 

rifabutin is not recommended. If

 

Elvitegravir (300 mg once daily)

Cmax: ↔*

 

the combination is needed, the

 

Ritonavir (100 mg once daily)

Cmin: ↔*

 

recommended dose of rifabut n

 

 

 

Rifabutin:

 

150 mg 3 times per week on set

 

 

 

 

days (for example M nday-

 

 

 

AUC: ↔**

 

Wednesday-Friday).

 

 

 

Cmax: ↔**

 

 

 

 

 

 

Cmin: ↔**

 

No dose adjustment of Vitekta is

 

 

 

 

 

required when co-administered

 

 

 

 

 

with reduced dose of rifabutin.

 

 

 

elvitegravir/rit navir longerDue to inhibition of CYP3A by

 

 

 

 

 

Fu ther dose reduction of rifabutin

 

 

 

 

 

has not b en studied. It should be

 

 

 

25-O-desacetyl-rifabutin:§

k pt in mind that a twice weekly

 

 

 

AUC: ↑ 851%**

dose of 150 mg may not provide

 

 

 

Cmax: ↑ 440%**

an optimal exposure to rifabutin

 

 

 

Cmin: ↑ 1,836%**

thus leading to a risk of rifamycin

 

 

 

*when compared to

resistance and a treatment failure.

 

 

 

 

 

 

 

 

 

no

§

 

 

 

 

 

 

 

 

 

 

300/100 mg o ce daily.

ritonavir, 25-O-desacetyl-rifabutin

 

 

product

 

exposure is increased.

 

 

 

**when compared to rifabutin

 

 

 

 

 

300 mg on e daily.

 

 

 

 

 

Total antimycobacterial activity

 

 

 

 

 

was increased by 50%.

 

 

 

ANTICOAGULANTS

 

 

 

 

 

 

Warfarin

 

Interaction not studied with

It is recommended that the

 

 

 

 

elvitegravir.

 

international normalised ratio

MedicinalElvitegravir (150 mg once daily)

AUC: ↔

 

(INR) be monitored upon

 

when Vitekta is co-administered

 

 

 

Concentrations of warfarin may

co-administration of Vitekta. INR

 

 

 

be affected upon

should continue to be monitored

 

 

 

co-administration with

during the first weeks following

 

 

 

elvitegravir.

 

cessation of treatment with

 

 

 

 

 

Vitekta.

 

H2-RECEPTOR ANTAGONISTS

 

 

 

 

 

Famot ne (40 mg once daily)

Elvitegravir:

 

No dose adjustment is required

 

 

Elvit gravir (150 mg once daily)

AUC: ↔

 

when Vitekta is co-administered

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

with famotidine.

 

 

 

Cmin: ↔

 

 

 

 

HMG-CoA REDUCTASE INHIBITORS

 

 

 

 

Rosuvastatin (10 mg single dose)

Elvitegravir:

 

No dose adjustment is required

 

 

Cobicistat (150 mg once daily)

Cmax: ↔

 

with rosuvastatin.

 

 

 

Cmin: ↔

 

 

 

 

 

 

Rosuvastatin:

 

 

 

 

 

AUC: ↑ 38%

 

 

 

 

 

Cmax: ↑ 89%

 

 

 

 

 

 

Cmin: ↑ 43%

 

 

 

 

Atorvastatin

Interaction not studied with

No dose adjustment is required

 

 

Fluvastatin

elvitegravir.

 

 

when Vitekta is co-administered

 

 

Pitavastatin

Plasma concentrations of OATP

with atorvastatin, fluvastatin,

 

 

Pravastatin

pitavastatin or pravastatin.

 

 

 

 

substrates are not expected to

 

 

 

 

 

 

 

change upon co-administration

 

 

 

 

 

 

 

of elvitegravir.

 

 

 

 

 

 

 

 

Plasma concentrations of

 

 

 

 

 

 

 

elvitegravir are not expected to

 

 

 

 

 

 

 

change upon co-administration

 

 

 

 

 

 

 

of OATP substrates/inhibitors.

 

 

 

 

 

ORAL CONTRACEPTIVES

 

 

 

 

 

 

 

 

Norgestimate (0.180/0.215 mg

Norgestimate:

 

Caution should be exercised when

 

 

once daily)

AUC: ↑ 126%

 

co-administering Vitekta and a

 

 

Ethinylestradiol (0.025 mg once

Cmax: ↑ 108%

 

 

hormonal contraceptive. The

 

 

daily)

Cmin: ↑ 167%

 

 

hormonal contraceptive sh uld

 

 

Elvitegravir (150 mg once daily)

 

 

 

contain at least 30 µg

 

 

Cobicistat (150 mg once daily)1

Ethinylestradiol:

 

ethinylestradiol and con ain

 

 

 

 

AUC: ↓ 25%

 

 

norgestimate as

he progestagen or

 

 

 

 

Cmax: ↔

 

 

patients sho ld

se an alternative

 

 

 

 

Cmin: ↓ 44%

 

 

reliable method of contraception

 

 

 

 

 

 

 

(see sections 4.4 and 4.6).

 

 

 

 

Elvitegravir:

 

 

 

authorised

 

 

 

 

AUC: ↔

 

 

The long-term effects of

 

 

 

 

Cmax: ↔

 

 

substantial increases in

 

 

 

 

Cmin: ↔

 

 

pro esterone exposure are

 

 

 

 

 

 

 

unknown. Co-administration of

 

 

 

 

 

 

 

elvitegravir with oral

 

 

 

 

 

 

 

contraceptives containing

 

 

 

 

 

 

 

progestagens other than

 

 

 

 

 

 

longer

 

 

 

 

 

 

 

 

 

norgestimate has not been studied

 

 

 

 

 

 

 

and therefore should be avoided.

 

 

PROTON PUMP INHIBITORS

 

no

 

 

 

 

 

 

Omeprazole (40 mg once daily)

Elvitegravir:

 

 

No dose adjustment is required

 

 

Elvitegravir (50 mg once daily

AUC: ↔

 

 

when Vitekta is co-administered

 

 

Ritonavir (100 mg once daily)

Cmax: ↔

 

 

with omeprazole.

 

 

 

 

Cmin: ↔

 

 

 

 

 

 

 

This study was conducted using the fixed- ose combination tablet elvitegravir/cobicistat/emtricitabine/tenofovir

 

 

 

 

disoproxil.

 

 

 

 

 

 

 

 

4.6 Fertility, pregnancy and lactation

 

 

 

 

 

 

 

Women of childbe ringproductpotential / contraception in males and females

 

 

 

 

The use of Vitekta must be accompanied by the use of effective contraception (see sections 4.4

 

and 4.5).

 

 

 

 

 

 

 

Medicinal

 

 

 

 

 

 

 

Pregnan y

There are no or limited clinical data with elvitegravir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects of elvitegravir with respect to reproductive toxicity. However, the maximum exposures evaluated in the rabbit were not in excess of those achieved therapeutically (see section 5.3).

Vitekta should not be used during pregnancy unless the clinical condition of the woman requires treatment with elvitegravir.

Breast-feeding

It is unknown whether elvitegravir/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of elvitegravir in milk. A risk to

Fertility
No human data on the effect of elvitegravir on fertility are available. harmful effects of elvitegravir on fertility.

the newborns/infants cannot be excluded. Therefore, Vitekta should not be used during breast- feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances.

Animal studies do not indicate

4.7 Effects on ability to drive and use machines

No studies on the effects of elvitegravir on the ability to drive and use machines have been performed.

4.8 Undesirable effects

authorised

Summary of the safety profile

 

Assessment of adverse reactions is based on data from a controlled clinical st dy (GS-US-183-0145) in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received elvitegravir

(n = 354) or raltegravir (n = 358) each administered with a background regimen consisting of a fully

active ritonavir-boosted protease inhibitor and other antiretrovirallongeragents. Of these 712 patients, 543

(269 elvitegravir and 274 raltegravir) and 439 (224 elvitegravir and 215 altegravir) received at least 48 and 96 weeks of treatment, respectively.

The most frequently reported adverse reactions to elvitegravir were diarrhoea (7.1%) and nausea (4.0%) (see Table 3).

Tabulated summary of adverse reactions

Adverse reactions to elvitegravir from clinical study experience are listed in Table 3 below, by body

system organ class and frequency. Within each frequency grouping, undesirable effects are presented

in order of decreasing seriousness. Frequencies are defined as common (≥ 1/100 to < 1/10) or

product

no

uncommon (≥ 1/1,000 to < 1/100).

Table 3: Tabulated summary of adverse reactions to elvitegravir based on experience for 96 weeks from clinical study GS-US-183-0145

 

Frequency

Adve se eaction

 

Psychiatric disorders:

 

Uncommon

suicidal ideation and suicide attempt (in patients with a pre-existing history of

 

 

 

Medicinal

depression or psychiatric illness), depression, insomnia

 

 

 

Nervous system disorders:

 

Common

headache

 

Uncommon

dizziness, paraesthesia, somnolence, dysgeusia

 

Gastro ntestinal disorders:

 

Common

abdominal pain, diarrhoea, vomiting, nausea

 

Uncommon

dyspepsia, abdominal distension, flatulence

 

Skin and subcutaneous

tissue disorders:

 

Common

rash

 

General disorders and administration site conditions:

 

Common

fatigue

Description of selected adverse reactions

Metabolic parameters

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

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) 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).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown

(see section 4.4).

authorised

 

Diarrhoea

In study GS-US-183-0145, diarrhoea was reported as an adverse reaction in 7.1% of subjects n the elvitegravir group and in 5.3% of subjects in the raltegravir group. In these subjects, diarrhoea was mild to moderate in severity and did not result in discontinuation of study drug.

Paediatric population

No data are available for children below 18 years of age. Vitekta is not recommended in this population (see section 4.2).

Reporting of suspected adverse reactions

longer

 

Reporting suspected adverse reactions after authorisation of the m dicinal p oduct is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

If overdose occurs the patient must be monitored f r evidence of toxicity. Treatment of overdose with

elvitegravir consists of general supportive measures i cluding monitoring of vital signs as well as

observation of the clinical status of the pa ie .

 

no

There is no specific antidote for overdose with elvitegravir. As elvitegravir is highly bound to plasma

proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic roperties

 

product

Pharmacother peutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX11.

Medicinal

Mechan sm of action and pharmacodynamic effects

Elv tegrav r is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Antiviral activity in vitro

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM). The in vitro antiviral activity of elvitegravir when combined with antiretroviral drugs from the nucleos(t)ide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI),

integrase strand transfer inhibitor, fusion inhibitor, or CCR5 co-receptor antagonist classes showed no antagonism.

Elvitegravir did not show inhibition of replication of HBV or HCV in vitro.

Resistance

In cell culture

HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture.

Phenotypic resistance to elvitegravir was most commonly associated with the primary integrase authorised

substitutions T66I, E92Q and Q148R. Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K.

Cross resistance

Elvitegravir-resistant viruses show varying degrees of cross-resistance to the integrase strand t ansfer inhibitor raltegravir depending on the type and number of substitutions. Viruses expressing the T66I/A substitutions maintain susceptibility to raltegravir, while most other patterns of elvitegravir-associated substitutions are associated with reduced susceptibility to ral egravir. With the exception of Y143C/R/H, HIV-1 with the primary raltegravir-associated substit ions T66K, Q148H/K/R, or N155H in integrase is associated with reduced susceptibility to elvitegravir.

In treatment-experienced patients

longer

In an analysis of HIV-1 isolates from treatment-failure subjects in study GS-US-183-0145 through

week 96, the development of one or more primary elvitegravir resistance-associated substitutions was observed in 23 of the 86 subjects with evaluable genotypic data from paired baseline and elvitegravir treatment-failure isolates (23/351 elvitegravir-treated subjects, 6.6%). Similar rates of raltegravir resistance development occurred in the HIV-1 from subjects treated with raltegravir (26/351 raltegravir-treated subjects, 7.4%). The most common substitutions that emerged in HIV-1 isolates from elvitegravir-treated subjects were T66I/A (n = 8), E92Q/G (n = 7), T97A (n = 4), S147G (n = 4), Q148R (n = 4), and N155H (n = 5) in integrase. In phen typic analyses of HIV-1 isolates with

resistance substitutions from elvitegravir-treated subjects, 14/20 (70%) had reduced susceptibility to

elvitegravir and 12/20 (60%) had reduced susceptibility to raltegravir.

Clinical experience

 

no

 

 

In treatment-experienced HIV-1 infected patients

 

product

 

The efficacy of elvitegravir is primarily based on the analyses through 96 weeks from one randomised, double-blind, active-contr lled stu y, study GS-US-183-0145, in treatment-experienced,

HIV-1 infected patients (n = 702).

In study GS-US-183-0145, atients were randomised in a 1:1 ratio to receive either elvitegravir Medicinal(150 mg or 85 mg) once daily or raltegravir 400 mg twice daily, each administered with a background regimen (BR) cont ining a fully-active ritonavir-boosted protease inhibitor (either atazanavir,

darunav r, fos mpren vir, lopinavir or tipranavir) and a second agent. The BR was selected by the investigator based on genotypic/phenotypic resistance testing and prior antiretroviral treatment history. Random sation was stratified by screening HIV-1 RNA level (≤ 100,000 copies/mL or

> 100,000 opies/mL) and the class of the second agent (NRTI or other classes). Virologic response rate was evaluated in both treatment arms. Virologic response was defined as achieving an

und tectable viral load (HIV-1 RNA < 50 copies/mL).

Baseline characteristics and treatment outcomes through 96 weeks for study GS-US-183-0145 are presented in Tables 4 and 5 respectively.

36

Table 4: Demographic and baseline disease characteristics of antiretroviral treatment- experienced HIV-1 infected adult subjects in study GS-US-183-0145

 

 

 

 

 

Elvitegravir + background

Raltegravir + background

 

 

 

 

 

 

 

 

regimen

 

 

 

 

regimen

 

 

 

 

 

 

 

 

n = 351

 

 

 

 

n = 351

 

 

 

Demographic characteristics

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Median age, years (min-max)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(20-78)

 

 

 

 

(19-74)

 

 

 

Sex

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Male

 

 

 

 

83.2%

 

 

 

 

80.9%

 

 

 

Female

 

 

 

 

16.8%

 

 

 

 

19.1%

 

 

 

Ethnicity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

White

 

 

 

 

60.1%

 

 

 

 

64.4%

 

 

 

Black/African American

 

 

35.6%

 

 

 

 

32.2%

 

 

 

Asian

 

 

 

 

2.6%

 

 

 

 

1.4%

 

 

 

Other

 

 

 

 

1.7%

 

 

 

 

2.0%

 

 

 

Baseline disease characteristics

 

 

 

 

 

 

 

 

 

 

 

 

 

Median baseline plasma

 

 

4.35

 

 

 

 

4.42

 

 

 

 

HIV-1 RNA (range)

 

 

 

(1.69-6.63)

 

 

 

(1.69-6.10)

 

 

 

log10 copies/mL

 

 

 

 

 

 

 

 

 

authorised

 

 

 

Percentage of subjects with

 

 

25.6

 

 

 

 

25.6

 

 

 

 

viral load > 100,000 copies/mL

 

 

 

 

 

 

 

 

 

 

 

 

 

Median baseline CD4+ cell

 

 

227.0

 

 

 

 

215.0

 

 

 

count (range), cells/mm3

 

(2.0-1,374.0)

 

 

 

(1.0-1,497.0)

 

 

 

Percentage of subjects with

 

 

44.4

longer

 

44.9

 

 

 

 

CD4+ cell counts

 

 

 

 

 

 

 

 

 

 

 

 

 

≤ 200 cells/mm3

 

 

 

 

 

 

 

 

 

 

 

 

 

Baseline genotypic sensitivity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

scorea

 

 

 

 

1%

 

 

 

 

< 1%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

no

 

 

 

 

15%

 

 

 

 

 

 

 

 

14%

 

 

 

 

 

 

 

 

 

 

 

 

81%

 

 

 

 

83%

 

 

 

 

 

 

 

 

3%

 

 

 

 

2%

 

 

 

 

a Genotypic sensitivity scores are calculated by summing up drug susceptibility values (1 = sensitive; 0 = reduced

 

susceptibility) on all drugs in the baseline background regimen.

 

 

 

 

 

 

 

 

 

 

Table 5: Virologic outcome of randomised treatment of study GS-US-183-0145 at week 48 and

 

week 96 (snapshot ana ysis)a

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

product

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Week 48

 

 

 

 

Week 96

 

 

 

 

 

Elvitegravir

 

Raltegravir

 

Elvitegravir

 

Raltegravir

 

 

 

 

 

+ background

 

+ background

 

+ background

 

+ background

 

 

 

 

 

 

regimen

 

regimen

 

regimen

 

regimen

 

 

 

 

 

 

n = 351

 

n = 351

 

n = 351

 

n = 351

 

 

Virologic success

 

 

60%

 

 

58%

 

52%

 

 

53%

 

 

 

HIV-1 RNA

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

< 50 copies/mL

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Treatment difference

 

 

2.2% (95% CI =

-5.0%, 9.3%)

 

-0.5% (95% CI = -7.9%, 6.8%)

 

 

Medicinal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

b

 

33%

 

 

32%

 

36%

 

 

31%

 

 

 

Virologic failure

 

 

 

 

 

 

 

 

 

 

No virologic data at

 

 

7%

 

 

11%

 

12%

 

 

16%

 

 

 

week 48 or week 96

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

window

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Discontinued study drug

 

2%

 

 

5%

 

 

3%

 

 

7%

 

 

 

due to AE or deathc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Discontinued study drug

 

4%

 

 

5%

 

 

8%

 

 

9%

 

 

 

 

Week 48

Week 96

 

 

 

Elvitegravir

Raltegravir

Elvitegravir

 

Raltegravir

 

 

 

+ background

+ background

+ background

 

+ background

 

 

 

regimen

regimen

regimen

 

regimen

 

 

 

n = 351

n = 351

n = 351

 

n = 351

 

 

due to other reasons and

 

 

 

 

 

 

 

last available

 

 

 

 

 

 

 

HIV-1 RNA

 

 

 

 

 

 

 

< 50 copies/mLd

 

 

 

 

 

 

 

Missing data during

1%

1%

1%

 

1%

 

 

window but on study

 

 

 

 

 

 

 

drug

 

 

 

 

 

 

a

Week 48 window is between day 309 and 364 (inclusive), week 96 window is between day 645 and 700 (inclu ve).

b Includes subjects who had ≥ 50 copies/mL in the week 48 or week 96 window, subjects who discontinued ea ly due to

 

lack or loss of efficacy, subjects who had a viral load ≥ 50 copies/mL at time of change in background regimen, subjects

 

who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at t e time f

 

discontinuation had a viral load of ≥ 50 copies/mL.

 

 

 

 

 

c

Includes patients who discontinued due to an AE or death at any time point from day 1 through e

ime window if this

 

resulted in no virologic data on treatment during the specified window.

authorised

dIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of effic cy, e.g., withdrew consent, loss to follow-up, etc.

Elvitegravir was non-inferior in achieving HIV-1 RNA <longer50 copies/mL when compared to raltegravir.

Among subjects with a genotypic sensitivity score of ≤ 1, 76% and 69% had HIV-1 RNA

< 50 copies/mL at week 48 in the elvitegravir and raltegravir treatment arms, respectively. Among subjects with a genotypic sensitivity score > 1, 57% and 56% had HIV-1 RNA < 50 copies/mL at week 48 in the elvitegravir and raltegravir treatment arms, respectively.

In study GS-US-183-0145, subgroup analyses noby co-administered protease inhibitor showed similar rates of virologic success for elvitegravir and raltegravir within each protease inhibitor subgroup at weeks 48 and 96 (HIV-1 RNA < 50 copies/mL) (Table 6).

In study GS-US-183-0145, the mean increase fr m baseline in CD4+ cell count at week 96 was

205 cells/mm3 in the elvitegravir-treated patie ts a d 198 cells/mm3 in the raltegravir-treated patients.

Table 6: Virologic success by co-a ministered protease inhibitor in study GS-US-183-0145 at week 48 and week 96 (snapsh t analysis)

 

 

product

 

Elvitegravir versus

 

 

 

raltegravir

 

HIV-1 RNA

 

Elvitegravir

Raltegravir

Difference in percentages

 

< 50 cop es/mL, /N (%)

(N = 351)

(N = 351)

(95% CI)a

 

Virolog c success at

 

 

 

 

 

 

week 48

 

 

 

 

 

 

Darunavir/ritonavir

 

126/202 (62.4%)

122/207 (58.9%)

3.4%

(-6.0% to 12.9%)

 

Lopinavir/ritonavir

 

39/68 (57.4%)

37/68 (54.4%)

2.9%

(-13.7% to 19.6%)

 

Atazanavir/ritonavir

 

34/61 (55.7%)

28/51 (54.9%)

0.8%

(-17.7% to 19.3%)

 

Fosamprenavir/ritonavir

8/14 (57.1%)

10/18 (55.6%)

1.6%

(-33.0% to 36.2%)

 

Tipranavir/ritonavir

 

3/6 (50.0%)

5/7 (71.4%)

-21.4% (-73.6% to 30.7%)

 

Virologic success at

 

 

 

 

 

Medicinal

 

 

 

 

 

 

week 96

 

 

 

 

 

 

Darunavir/ritonavir

 

105/202 (52.0%)

112/207 (54.1%)

-2.1% (-11.8% to 7.5%)

 

Lopinavir/ritonavir

 

36/68 (52.9%)

37/68 (54.4%)

-1.5% (-18.2% to 15.3%)

 

Atazanavir/ritonavir

 

33/61 (54.1%)

23/51 (45.1%)

9.0%

(-9.5% to 27.5%)

 

Fosamprenavir/ritonavir

7/14 (50.0%)

11/18 (61.1%)

-11.1% (-45.7% to 23.4%)

 

Tipranavir/ritonavir

 

3/6 (50.0%)

3/7 (42.9%)

7.1%

(-47.1% to 61.4%)

aThe difference in proportions and its 95% CIs between randomised treatment groups is based on normal approximation.

Although limited by the small number of female subjects in study GS-US-183-0145, subgroup analysis by gender showed that the rates of virologic success in female subjects at weeks 48 and 96 (HIV-1 RNA < 50 copies/mL) were numerically lower in the elvitegravir treatment arm than in the raltegravir treatment arm. Virologic success rates at week 48 for elvitegravir and raltegravir were 47.5% (28/59) and 62.7% (42/67) (difference: -12.3% [95% CI: -30.1% to 5.5%]), respectively, for female subjects, and 62.3% (182/292) and 56.3% (160/284) (difference: 5.3% [95% CI: -2.5% to 13.2%]), respectively, for male subjects. Virologic success rates at week 96 for elvitegravir and

raltegravir were 39.0% (23/59) and 52.2% (35/67) (difference: -8.4% [95% CI: -26.1% to 9.2%]), authorised

respectively, for female subjects, and 55.1% (161/292) and 53.2% (151/284) (difference: 1.5% [95% CI: -6.5% to 9.6%]), respectively, for male subjects.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies w th elvitegravir in one or more subsets of the paediatric population in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration of ritonavir-boosted elvitegravirlongerwith food in HIV-1 infected subjects,

elvitegravir peak plasma concentrations were observed 4 hours post-dose. The steady-state mean Cmax,

AUCtau, and Ctrough (mean ± SD) following multiple doses of elvit ravir plus a ritonavir-boosted protease inhibitor (150 mg elvitegravir with darunavir or fosamprenavir; 85 mg elvitegravir with

atazanavir or lopinavir) in HIV-1 infected subjects were 1.4 ± 0.39 μg/mL, 18 ± 6.8 μg•h/mL, and 0.38 ± 0.22 μg/mL for elvitegravir, respectively. The abs lute ral bioavailability has not been determined.

150 mg elvitegravir/150 mg cobicistat/200 mgnoemtricitabine/245 mg tenofovir disoproxil with a light

Relative to fasting conditions, the administration f b sted elvitegravir as the fixed-dose combination

meal (approximately 373 kcal, 20% fat) or high-fat meal (approximately 800 kcal, 50% fat) resulted in increased exposures of productelvitegravir. The Cmax and AUCtau of elvitegravir increased 22% and 36% with a light meal, while increasing 56% and 91% with a high-fat meal, respectively.

Distribution

Elvitegravir is 98-99% bound to human plasma proteins and the binding is independent of drug concentration over the range f 1.0 ng/mL to 1.6 µg/mL. The mean plasma to blood drug concentration ratio is 1.37.

MedicinalBiotransformation

Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation via UGT1A1/3 e zymes (minor route).

Ritonav r nhibits CYP3A, thereby substantially increasing the plasma concentrations of elvitegravir. A m n stration of once-daily ritonavir (20-200 mg) results in an increased elvitegravir exposure following repeat once-daily administration, with elvitegravir exposure reaching a plateau with approximately 100 mg of ritonavir. Further increases in ritonavir dose do not result in further

incr ases in elvitegravir exposure. Vitekta is indicated for use only when co -administered with ritonavir as a boosting agent.

Mean steady-state exposure (AUCtau) of unboosted elvitegravir is ~ 20% lower after multiple dosing versus a single dose, indicating modest autoinduction of its metabolism. Upon boosting with ritonavir (100 mg), net inhibition of elvitegravir metabolism is observed with significantly increased systemic exposures (20-fold higher AUC), high trough concentrations, and longer median elimination half-life (9.5 versus 3.5 hours).

Following oral administration of a single dose of ritonavir-boosted [14C]elvitegravir, elvitegravir was the predominant species in plasma, representing approximately 94% and 61% of the circulating radioactivity at 32 and 48 hours, respectively. Metabolites produced by aromatic and aliphatic hydroxylation or glucuronidation are present in very low levels and do not contribute to the overall antiviral activity of elvitegravir.

Elimination

Following oral administration of ritonavir-boosted [14C]elvitegravir, 94.8% of the dose was recovered

in faeces, consistent with the hepatobiliary elimination of elvitegravir; 6.7% of the administered dose authorised

was recovered in urine as metabolites. The median terminal plasma half-life of ritonavir-boosted elvitegravir is approximately 8.7 to 13.7 hours.

Linearity/non-linearity

Elvitegravir plasma exposures are non-linear and less than dose-proportional, likely due to solub l ty- limited absorption.

Elderly

Pharmacokinetics of elvitegravir have not been fully evaluated in the elderly (over 65 years of age).

Gender

No clinically relevant pharmacokinetic differences due to gender have been identified for boosted

elvitegravir.

longer

 

Ethnicity

No clinically relevant pharmacokinetic differences due to eth icity have been identified for boosted elvitegravir.

Paediatric population

Renal impairmentno

The pharmacokinetics of elvitegravir in paediatric subjects have not been established.

renal impairment and healthyproductsubjects. No dose adjustment of Vitekta is required for patients with renal impairment.

A study of the pharmacokinetics of boos ed elvi egravir was performed in non HIV-1 infected subjects with severe renal impairment (estimated reatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with severe

Hepatic impairment

MedicinalElvitegravir is primari y metabolised and eliminated by the liver. A study of the pharmacokinetics of boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment

(Child-Pugh Cl ss B). No clinically relevant differences in elvitegravir pharmacokinetics were

observed between subjects with moderate impairment and healthy subjects. No dose adjustment of Vitekta s e essary for patients with mild to moderate hepatic impairment. The effect of severe

hepat mpairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir has not been studied.

Hepatitis B and/or hepatitis C virus co-infection

Limited data from population pharmacokinetic analysis (n = 56) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of boosted elvitegravir.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. The maximum doses of elvitegravir tested in the development toxicity studies in rats and rabbits corresponded to exposures that are approximately 29-fold and 0.2-fold the human therapeutic exposure, respectively.

Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in an

in vivo rat micronucleus assay at doses up to 2,000 mg/kg. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.

Elvitegravir did not show any carcinogenic potential in long-term oral carcinogenicity studies in mice and rats.

The active substance elvitegravir is persistent in the environment.

authorised

6.

PHARMACEUTICAL PARTICULARS

 

 

 

6.1

List of excipients

 

 

 

Tablet core

 

 

 

Croscarmellose sodium

 

 

 

Hydroxypropyl cellulose

 

 

 

Lactose monohydrate

 

 

 

Magnesium stearate

 

 

 

Microcrystalline cellulose

 

longer

 

Sodium lauryl sulfate

 

 

 

 

 

Film-coating

 

 

 

Indigo carmine aluminium lake (E132)

 

 

 

Macrogol 3350 (E1521)

 

 

 

Polyvinyl alcohol (partially hydrolysed) (E1203)

 

 

Talc (E553B)

no

 

 

Titanium dioxide (E171)

 

 

Iron oxide yellow (E172)

 

 

6.2

Incompatibilities

 

 

Not applicable.

6.3 Shelf life

4 years.

product

 

Medicinal

 

6.4

Special precautions for storage

This med c l product does not require any special storage conditions.

6.5

Nature and contents of container

High

ensity polyethylene (HDPE) bottle with a child-resistant closure containing 30 film-coated

tabl ts.

 

Pack size: 1 bottle of 30 film-coated tablets.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Gilead Sciences International Limited Cambridge
CB21 6GT United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/883/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 November 2013

10. DATE OF REVISION OF THE TEXT

 

authorised

 

 

 

 

Detailed information on this medicinal product is available on the w bsite of the European Medicines

Agency http://www.ema.europa.eu.

 

longer

 

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

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