Edurant 25 mg tablets - United Kingdom[英国药品]

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Edurant 25 mg tablets

2016-11-29 07:05:05 来源: 作者: 【大中小】浏览:487次评论:0条

1. Name of the medicinal product

EDURANT 25 mg film-coated tablets

2. Qualitative and quantitative composition

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.

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 patients 12 years of age and older with a viral load ≤ 100,000 HIV-1 RNA copies/ml.

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

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 the medicine 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 the medicine, another EDURANT tablet should be taken with a meal. If a patient vomits more than 4 hours after taking the medicine, 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 older patients (see section 5.2). EDURANT should be used with caution in this population.

Renal impairment

EDURANT has mainly been studied in patients with normal renal function. No dose adjustment of rilpivirine is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of rilpivirine 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 rilpivirine 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).

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).

Paediatric population

The safety and efficacy of EDURANT in children aged < 12 years have not yet been established.

No data are available.

Method of administration

EDURANT must be taken orally, once daily with a meal (see section 5.2). It is recommended that the 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 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).

4.4 Special warnings and precautions for use

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

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 in adults through 96 weeks, patients treated with rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with rilpivirine versus 7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml (5.7% with rilpivirine versus 3.6% with efavirenz). The greater risk of virologic failure for patients in the rilpivirine 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 rilpivirine than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1).

Findings in adolescents (12 to less than 18 years of age) in trial C213 were generally in line with these data (for details see section 5.1).

Only adolescents deemed likely to have good adherence to antiretroviral therapy should be treated with rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment options.

As with other antiretroviral medicinal products, resistance testing should guide the use of rilpivirine (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.

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.

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 rilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine.

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

Co-administration of rilpivirine 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

Rilpivirine 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 medicines 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

Interaction studies have only been performed in adults.

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”).

Table 1: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by therapeutic areas	Interaction Geometric mean change (%)	Recommendations concerning co-administration
ANTI-INFECTIVES
Antiretrovirals
HIV NRTIs/N[t]RTIs
Didanosine*^# 400 mg once daily	didanosine AUC ↑ 12% didanosine C_min NA didanosine C_max↔ rilpivirine AUC ↔ rilpivirine C_min↔ rilpivirine C_max↔	No dose adjustment is required. Didanosine should be administered at least two hours before or at least four hours after rilpivirine.
Tenofovir disoproxil fumarate*^# 300 mg once daily	tenofovir AUC ↑ 23% tenofovir C_min↑ 24% tenofovir C_max↑ 19% rilpivirine AUC ↔ rilpivirine C_min↔ rilpivirine C_max↔	No dose adjustment is required.
Other NRTIs (abacavir, emtricitabine, lamivudine, stavudine and zidovudine)	Not studied. No clinically relevant drug-drug interactions are expected.	No dose adjustment is required.
HIV NNRTIs
NNRTIs (delavirdine, efavirenz, etravirine, nevirapine)	Not studied.	It is not recommended to co-administer rilpivirine with other NNRTIs.
HIV PIs – with co-administration of low dose ritonavir
Darunavir/ritonavir*^# 800/100 mg once daily	darunavir AUC ↔ darunavir C_min↓ 11% darunavir C_max↔ rilpivirine AUC ↑ 130% rilpivirine C_min↑ 178% rilpivirine C_max↑ 79% (inhibition of CYP3A enzymes)	Concomitant use of rilpivirine with ritonavir-boosted PIs causes an increase in the plasma concentrations of rilpivirine, but no dose adjustment is required.
Lopinavir/ritonavir (soft gel capsule)*^# 400/100 mg twice daily	lopinavir AUC ↔ lopinavir C_min↓ 11% lopinavir C_max↔ rilpivirine AUC ↑ 52% rilpivirine C_min↑ 74% rilpivirine C_max↑ 29% (inhibition of CYP3A enzymes)
Other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir)	Not studied.
HIV PIs – without co-administration of low dose ritonavir
Unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir)	Not studied. Increased exposure of rilpivirine is expected. (inhibition of CYP3A enzymes)	No dose adjustment is required.
CCR5 Antagonists
Maraviroc	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
HIV Integrase Strand Transfer Inhibitors
Raltegravir*	raltegravir AUC ↑ 9% raltegravir C_min↑ 27% raltegravir C_max↑ 10% rilpivirine AUC ↔ rilpivirine C_min↔ rilpivirine C_max↔	No dose adjustment is required.
Other Antiviral Agents
Ribavirin	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
Telaprevir* 750 mg every 8 hours	telaprevir AUC ↓ 5% telaprevir C_min↓ 11% telaprevir C_max↓ 3% rilpivirine AUC ↑ 78% rilpivirine C_min↑ 93% rilpivirine C_max↑ 49%	No dose adjustment is required.
OTHER AGENTS
ANTICONVULSANTS
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)	Rilpivirine must not be used in combination with these anticonvulsants as co-administration may result in loss of therapeutic effect of rilpivirine (see section 4.3).
AZOLE ANTIFUNGAL AGENTS
Ketoconazole*^# 400 mg once daily	ketoconazole AUC ↓ 24% ketoconazole C_min↓ 66% ketoconazole C_max↔ (induction of CYP3A due to high rilpivirine dose in the study) rilpivirine AUC ↑ 49% rilpivirine C_min↑ 76% rilpivirine C_max↑ 30% (inhibition of CYP3A enzymes)	At the recommended dose of 25 mg once daily, no dose adjustment is required when rilpivirine is co-administered with ketoconazole.
Fluconazole Itraconazole Posaconazole Voriconazole	Not studied. Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine. (inhibition of CYP3A enzymes)	No dose adjustment is required.
ANTIMYCOBACTERIALS
Rifabutin* 300 mg once daily^†	rifabutin AUC ↔ rifabutin C_min↔ rifabutin C_max↔ 25-O-desacetyl-rifabutin AUC ↔ 25-O-desacetyl-rifabutin C_min↔ 25-O-desacetyl-rifabutin C_max↔	Throughout co-administration of rilpivirine with rifabutin, the rilpivirine dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily.
300 mg once daily (+ 25 mg once daily rilpivirine)	rilpivirine AUC ↓ 42% rilpivirine C_min↓ 48% rilpivirine C_max↓ 31%
300 mg once daily (+ 50 mg once daily rilpivirine)	rilpivirine AUC ↑ 16%* rilpivirine C_min↔* rilpivirine C_max↑ 43%* * compared to 25 mg once daily rilpivirine alone (induction of CYP3A enzymes)
Rifampicin*^# 600 mg once daily	rifampicin AUC ↔ rifampicin C_min NA rifampicin C_max↔ 25-desacetyl-rifampicin AUC ↓ 9% 25-desacetyl-rifampicin C_min NA 25-desacetyl-rifampicin C_max↔ rilpivirine AUC ↓ 80% rilpivirine C_min↓ 89% rilpivirine C_max↓ 69% (induction of CYP3A enzymes)	Rilpivirine must not be used in combination with rifampicin as co-administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).
Rifapentine	Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)	Rilpivirine must not be used in combination with rifapentine as co-administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).
MACROLIDE ANTIBIOTICS
Clarithromycin Erythromycin	Not studied. Increased exposure of rilpivirine is expected. (inhibition of CYP3A enzymes)	Where possible, alternatives such as azithromycin should be considered.
GLUCOCORTICOIDS
Dexamethasone (systemic, except for single dose use)	Not studied. Dose dependent decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)	Rilpivirine should not be used in combination with systemic dexamethasone (except as a single dose) as co-administration may result in loss of therapeutic effect of rilpivirine (see section 4.3). Alternatives should be considered, particularly for long-term use.
PROTON PUMP INHIBITORS
Omeprazole*^# 20 mg once daily	omeprazole AUC ↓ 14% omeprazole C_min NA omeprazole C_max↓ 14% rilpivirine AUC ↓ 40% rilpivirine C_min↓ 33% rilpivirine C_max↓ 40% (reduced absorption due to gastric pH increase)	Rilpivirine must not be used in combination with proton pump inhibitors as co-administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).
Lansoprazole Rabeprazole Pantoprazole Esomeprazole	Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (reduced absorption due to gastric pH increase)
H₂-RECEPTOR ANTAGONISTS
Famotidine*^# 40 mg single dose taken 12 hours before rilpivirine	rilpivirine AUC ↓ 9% rilpivirine C_min NA rilpivirine C_max↔	The combination of rilpivirine and H₂-receptor antagonists should be used with particular caution. Only H_2-receptor antagonists that can be dosed once daily should be used. A strict dosing schedule, with intake of H_2-receptor antagonists at least 12 hours before or at least 4 hours after rilpivirine should be used.
Famotidine*^# 40 mg single dose taken 2 hours before rilpivirine	rilpivirine AUC ↓ 76% rilpivirine C_min NA rilpivirine C_max↓ 85% (reduced absorption due to gastric pH increase)
Famotidine*^# 40 mg single dose taken 4 hours after rilpivirine	rilpivirine AUC ↑ 13% rilpivirine C_min NA rilpivirine C_max↑ 21%
Cimetidine Nizatidine Ranitidine	Not studied. (reduced absorption due to gastric pH increase)
ANTACIDS
Antacids (e.g., aluminium or magnesium hydroxide, calcium carbonate)	Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (reduced absorption due to gastric pH increase)	The combination of rilpivirine and antacids should be used with particular caution. Antacids should only be administered either at least 2 hours before or at least 4 hours after rilpivirine.
NARCOTIC ANALGESICS
Methadone* 60-100 mg once daily, individualised dose	R(-) methadone AUC ↓ 16% R(-) methadone C_min↓ 22% R(-) methadone C_max↓ 14% rilpivirine AUC ↔* rilpivirine C_min↔* rilpivirine C_max↔* * based on historic controls	No dose adjustments are required when initiating co-administration of methadone with rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
ANTIARRHYTHMICS
Digoxin*	digoxin AUC ↔ digoxin C_min NA digoxin C_max↔	No dose adjustment is required.
ANTICOAGULANTS
Dabigatran etexilate	Not studied. A risk for increases in dabigatran plasma concentrations cannot be excluded. (inhibition of intestinal P-gp)	The combination of rilpivirine and dabigatran etexilate should be used with caution.
ANTIDIABETICS
Metformin* 850 mg single dose	metformin AUC ↔ metformin C_min NA metformin C_max↔	No dose adjustment is required.
HERBAL PRODUCTS