EDURANT 25 mg film-coated tablets

Each film-coated tablet contains rilpivirine hydrochloride equivalent to 25 mg rilpivirine.

Excipient with known effect: each film-coated tablet contains 56 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet

White to off-white, round, biconvex, film-coated tablet with a diameter of 6.4 mm, debossed with “TMC” on one side and “25” on the other side.

EDURANT, in combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve adult patients with a viral load ≤ 100,000 HIV-1 RNA copies/ml.

As with other antiretroviral medicinal products, genotypic resistance testing should guide the use of EDURANT (see sections 4.4 and 5.1).

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

Posology

EDURANT must always be given in combination with other antiretroviral medicinal products.

Adults

The recommended dose of EDURANT is one 25 mg tablet taken once daily. EDURANT must be taken with a meal (see section 5.2).

Dose adjustment

For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) taken once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily (see section 4.5).

Missed dose

If the patient misses a dose of EDURANT within 12 hours of the time it is usually taken, the patient must take EDURANT with a meal as soon as possible and resume the normal dosing schedule. If a patient misses a dose of EDURANT by more than 12 hours, the patient should not take the missed dose, but resume the usual dosing schedule.

If a patient vomits within 4 hours of taking EDURANT, another EDURANT tablet should be taken with a meal. If a patient vomits more than 4 hours after taking EDURANT, the patient does not need to take another dose of EDURANT until the next regularly scheduled dose.

Special populations

Older people

There is limited information regarding the use of EDURANT in patients > 65 years of age. No dose adjustment of EDURANT is required in older patients (see section 5.2). EDURANT should be used with caution in this population.

Paediatric population

The safety and efficacy of EDURANT in children aged < 18 years have not yet been established.

No data are available.

Hepatic impairment

There is limited information regarding the use of EDURANT in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). No dose adjustment of EDURANT is required in patients with mild or moderate hepatic impairment. EDURANT should be used with caution in patients with moderate hepatic impairment. EDURANT has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, EDURANT is not recommended in patients with severe hepatic impairment (see section 5.2).

Renal impairment

EDURANT has mainly been studied in patients with normal renal function. No dose adjustment of EDURANT is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, EDURANT should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of EDURANT with a strong CYP3A inhibitor (e.g., ritonavir-boosted HIV protease inhibitor) should only be used if the benefit outweighs the risk (see section 5.2).

Treatment with EDURANT resulted in an early small increase of mean serum creatinine levels which remained stable over time and is not considered clinically relevant (see section 4.8).

Method of administration

EDURANT must be taken orally, once daily with a meal (see section 5.2). It is recommended that the EDURANT film-coated tablet be swallowed whole with water and not be chewed or crushed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

EDURANT should not be co-administered with the following medicinal products, as significant decreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of EDURANT (see section 4.5):

- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

- the antimycobacterials rifampicin, rifapentine

- proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole

- the systemic glucocorticoid dexamethasone, except as a single dose treatment

- St John's wort (Hypericum perforatum).

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.

Virologic failure and development of resistance

EDURANT has not been eva luated in patients with previous virologic failure to any other antiretroviral therapy. The list of rilpivirine resistance-associated mutations presented in section 5.1 should only guide the use of EDURANT in the treatment-naïve population.

In the pooled efficacy analysis from the Phase III trials through 96 weeks, patients treated with EDURANT with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with EDURANT versus 7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml (5.7% with EDURANT versus 3.6% with efavirenz). The greater risk of virologic failure for patients in the EDURANT arm was observed in the first 48 weeks of these trials (see section 5.1). Patients with a baseline viral load > 100,000 HIV-1 RNA copies/ml who experienced virologic failure exhibited a higher rate of treatment-emergent resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. More patients who failed virologically on EDURANT than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1).

As with other antiretroviral medicinal products, resistance testing should guide the use of EDURANT (see section 5.1).

Cardiovascular

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8 and 5.2). EDURANT at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. EDURANT should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

Fat redistribution

Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug-related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution (see section 4.8).

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 pathogens may arise and cause serious clinical conditions or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary.

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

Important information about some of the ingredients of EDURANT

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

Medicinal products that affect rilpivirine exposure

Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of EDURANT and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of EDURANT.

Co-administration of EDURANT and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.

Co-administration of EDURANT with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of EDURANT.

Medicinal products that are affected by the use of rilpivirine

EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P-glycoprotein in vitro (IC₅₀ is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other drugs transported by P-glycoprotein that are more sensitive to intestinal P-gp inhibition, e.g. dabigatran etexilate.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC₅₀ of < 2.7 nM. The clinical implications of this finding are currently unknown.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in table 1.

Interaction table

Interactions between rilpivirine and co-administered medicinal products are listed in table 1 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”).

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