1. Name Of The Medicinal Product
EDURANT
2. Qualitative And Quantitative Composition
Each film-coated tablet contains rilpivirine hydrochloride equivalent to 25 mg rilpivirine.
Excipient: each film-coated tablet contains 56 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
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.
4. Clinical Particulars
4.1 Therapeutic Indications
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
This indication is based on week 48 safety and efficacy analyses from two randomised, double-blind, controlled, Phase III trials in treatment-naïve patients and week 96 safety and efficacy analyses from a Phase IIb trial in treatment-naïve patients (see section 5.1).
As with other antiretroviral medicinal products, genotypic resistance testing should guide the use of EDURANT (see sections 4.4 and 5.1).
4.2 Posology And Method Of Administration
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).
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
Elderly
There is limited information regarding the use of EDURANT in patients > 65 years of age. No dose adjustment of EDURANT is required in elderly 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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
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:
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifabutin, 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).
4.4 Special Warnings And Precautions For Use
Patients should be advised that current antiretroviral therapy does not cure HIV, and there is still a risk of passing HIV to others through sexual contact or contamination with blood when taking EDURANT. Appropriate precautions to prevent the transmission of HIV should continue to be employed.
Virologic failure and development of resistance
EDURANT has not been evaluated 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 analysis from the Phase III trials, patients treated with EDURANT with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (15.1% with EDURANT versus 6.3% efavirenz arm) compared to patients with a baseline viral load
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 evaluation 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 institution 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 evaluated and treatment instituted when necessary (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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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. The clinical relevance of this inhibition is unknown. EDURANT may inhibit intestinal P-glycoprotein and affect medicinal products that are transported by P-glycoprotein in the intestine, such as dabigatran. This may lead to increased plasma concentrations of such medicinal products.
Rilpivirine inhibits the active renal tubular secretion of creatinine. Via the same mechanism exposure to metformin may be increased. Patients should be carefully monitored when initiating or stopping the concomitant administration of rilpivirine and metformin.
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 “
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* The interaction between EDURANT and the medicinal product was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
# This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of EDURANT of 25 mg once daily.
QT prolonging medicinal products
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). EDURANT should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate and well controlled or pharmacokinetic studies with EDURANT in pregnant women. Studies in animals have shown no reproductive toxicity (see section 5.3) and limited placenta passage. It is not known whether placental transfer of EDURANT occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits.
EDURANT should not be used during pregnancy unless clearly needed.
Breastfeeding
It is not known whether rilpivirine is excreted in human milk. EDURANT is excreted in the milk of rats. Because of both the potential for HIV transmission and the potential for adverse reactions in breastfed infants, mothers should be instructed not to breastfeed if they are receiving EDURANT.
Fertility
No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects on fertility were seen in animal studies (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
EDURANT has no or negligible influence on the ability to drive and use machines. No studies on the effects of EDURANT on the ability to drive and use machines have been performed. Fatigue, dizziness and somnolence have been reported in some patients taking EDURANT and should be considered when assessing a patient's ability to drive or operate machinery.
4.8 Undesirable Effects
Summary of the safety profile
The safety assessment is based on pooled data from 1,368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) (see section 5.1). The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 55.7 and 55.6 weeks, respectively.
Tabulated summary of adverse reactions
Clinical ADRs reported in adult patients treated with EDURANT are summarised in table 2. Selected treatment emergent clinical laboratory abnormalities, considered as ADRs, are included in a paragraph below table 2. The ADRs are listed by system organ class (SOC) and frequency. Frequencies are defined as very common (
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BR=background regimen
N=number
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