rilpivirine hydrochloride
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Indications and Usage for Edurant
Edurant™, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve adult patients.
This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects and Week 96 safety and efficacy analyses from a Phase 2b trial in treatment-naïve subjects [see Clinical Studies (14.1)].
The following points should be considered when initiating therapy with Edurant:
- More Edurant treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy [see Clinical Studies (14.1)].
- The observed virologic failure rate in Edurant treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [see Clinical Pharmacology (12.4)].
- More subjects treated with Edurant developed lamivudine/emtricitabine associated resistance compared to efavirenz [see Clinical Pharmacology (12.4)].
Edurant Dosage and Administration
The recommended dose of Edurant is one 25 mg tablet once daily taken orally with a meal [see Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with "TMC" on one side and "25" on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.
Contraindications
Edurant should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Edurant or to the class of NNRTIs [see also Drug Interactions (7) and Clinical Pharmacology (12.3)]:
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifabutin, rifampin, rifapentine
- proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St John's wort (Hypericum perforatum)
Warnings and Precautions
Drug Interactions
Caution should be given to prescribing Edurant with drugs that may reduce the exposure of rilpivirine [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)].
In 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 electrocardiogram [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. Edurant should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with Edurant. During the Phase 3 trials (N = 1368), the incidence of depressive disorders (regardless of causality, severity) reported among Edurant (n = 686) or efavirenz (n = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both Edurant and efavirenz. The incidence of discontinuation due to depressive disorders among Edurant or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the Edurant arm while suicide ideation was reported in 1 subject in the Edurant arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Edurant, and if so, to determine whether the risks of continued therapy outweigh the benefits.
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Edurant. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.
Adverse Reactions
The following adverse drug reaction (ADR) is discussed in greater detail in other sections of the package insert:
- Depressive Disorders [see Warnings and Precautions (5.2)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety assessment is based on pooled data from 1368 patients in the Phase 3 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 Clinical Studies (14.1)]. The median duration of exposure for patients in the Edurant arm and efavirenz arm was 55.7 and 55.6 weeks, respectively. The proportion of subjects who discontinued treatment with Edurant or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the Edurant arm and 15 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the Edurant arm and 10 (1.5%) subjects in the efavirenz arm.
Common Adverse Drug Reactions
Clinical ADRs of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.
| System Organ Class, Preferred Term, % | Pooled Data from the TMC278-C209 and TMC278-C215 Trials | |
|---|---|---|
| Edurant + BR N=686 | Efavirenz + BR N=682 | |
| N=total number of subjects per treatment group, BR=background regimen | ||
| ||
| Gastrointestinal Disorders | ||
| Nausea | 1% | 3% |
| Abdominal pain | 1% | 2% |
| Vomiting | 1% | 2% |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 1% | 2% |
| Nervous System Disorders | ||
| Headache | 3% | 3% |
| Dizziness | 1% | 7% |
| Psychiatric Disorders | ||
| Depressive disorders† | 4% | 3% |
| Insomnia | 3% | 3% |
| Abnormal dreams | 1% | 4% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 3% | 11% |
There were no additional ADR terms identified in adult subjects in the Phase 2b TMC278-C204 trial through 192 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials.
Less Common Adverse Drug Reactions
Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Edurant are listed below by Body System. Some of these events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with Edurant.
Gastrointestinal Disorders: diarrhea, abdominal discomfort
Hepatobiliary Disorders: cholecystitis, cholelithiasis
Metabolism and Nutrition Disorders: decreased appetite
Nervous System: somnolence
Psychiatric Disorder: sleep disorders, anxiety
Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative
Laboratory Abnormalities in Treatment-Naïve Subjects
The percentage of subjects treated with Edurant or efavirenz in the Phase 3 trials with selected treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2.
| Laboratory Parameter Abnormality, (%) | DAIDS Toxicity Range | Pooled Data from the TMC278-C209 and TMC278-C215 Trials | |
|---|---|---|---|
| Edurant + BR N=686 | Efavirenz + BR N=682 | ||
| BR = background regimen; ULN = upper limit of normal | |||
| N = number of subjects per treatment group | |||
| Note: Percentages were calculated versus the number of subjects in ITT. | |||
| BIOCHEMISTRY | |||
| Increased Creatinine | |||
| Grade 1 | ≥ 1.1–≤ 1.3 × ULN | 5% | <1% |
| Grade 2 | > 1.3–≤ 1.8 × ULN | <1% | <1% |
| Grade 3 | > 1.8–≤ 3.4 × ULN | 0 | 0 |
| Grade 4 | > 3.4 × ULN | 0 | <1% |
| Increased AST | |||
| Grade 1 | ≥ 1.25–≤ 2.5 × ULN | 12% | 16% |
| Grade 2 | > 2.5–≤ 5.0 × ULN | 3% | 6% |
| Grade 3 | > 5.0–≤ 10.0 × ULN | 2% | 2% |
| Grade 4 | > 10.0 × ULN | <1% | <1% |
| Increased ALT | |||
| Grade 1 | ≥ 1.25–≤ 2.5 × ULN | 15% | 18% |
| Grade 2 | > 2.5–≤ 5.0 × ULN | 4% | 6% |
| Grade 3 | > 5.0–≤ 10.0 × ULN | <1% | 2% |
| Grade 4 | > 10.0 × ULN | <1% | 1% |
| Increased Total Bilirubin | |||
| Grade 1 | ≥ 1.1–≤ 1.5 × ULN | 5% | <1% |
| Grade 2 | > 1.5–≤ 2.5 × ULN | 2% | <1% |
| Grade 3 | > 2.5–≤ 5.0 × ULN | <1% | <1% |
| Grade 4 | > 5.0 × ULN | 0 | 0 |
| Increased Total Cholesterol (fasted) | |||
| Grade 1 | 5.18–6.19 mmol/L 200–239 mg/dL | 14% | 28% |
| Grade 2 | 6.20–7.77 mmol/L 240–300 mg/dL | 5% | 16% |
| Grade 3 | > 7.77 mmol/L > 300 mg/dL | <1% | 2% |
| Increased LDL Cholesterol (fasted) | |||
| Grade 1 | 3.37–4.12 mmol/L 130–159 mg/dL | 12% | 23% |
| Grade 2 | 4.13–4.90 mmol/L 160–190 mg/dL | 5% | 11% |
| Grade 3 | > 4.91 mmol/L > 191 mg/dL | <1% | 4% |
| Increased Triglycerides (fasted) | |||
| Grade 2 | 5.65–8.48 mmol/L 500–750 mg/dL | 2% | 2% |
| Grade 3 | 8.49–13.56 mmol/L 751–1,200 mg/dL | < 1% | 2% |
| Grade 4 | > 13.56 mmol/L > 1,200 mg/dL | 0 | < 1% |
Adrenal Function
In the pooled Phase 3 trials, at Week 48, the overall mean change from baseline in basal cortisol showed a decrease of -13.1 nmol/L in the Edurant group, and an increase of +9.0 nmol/L in the efavirenz group. At Week 48, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the Edurant group (+16.5 ± 6.14 nmol/L) than in the efavirenz group (+58.1 ± 6.66 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 48 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
Serum Creatinine
Increases in serum creatinine occurred within the first four weeks of treatment and remained stable through 48 weeks. A mean change of 0.09 mg/dL (range: -0.20 mg/dL to 0.62 mg/dL) was observed after 48 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.
Serum Lipids
Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 3.
| Pooled data from the TMC278-C209 and TMC278-C215 trials | ||||||||
|---|---|---|---|---|---|---|---|---|
| Edurant + BR | Efavirenz + BR | |||||||
| N | Baseline | Week 48 | N | Baseline | Week 48 | |||
| Mean (95% CI) | Mean (mg/dL) | Mean (mg/dL) | Mean Change† (mg/dL) | Mean (mg/dL) | Mean (mg/dL) | Mean Change† (mg/dL) | ||
| N = number of subjects per treatment group | ||||||||
| ||||||||
| Total Cholesterol (fasted) | 584 | 161 | 163 | 2 | 549 | 160 | 187 | 27 |
| HDL-cholesterol (fasted) | 582 | 41 | 45 | 4 | 548 | 40 | 50 | 10 |
| LDL-cholesterol (fasted) | 580 | 96 | 95 | -1 | 547 | 95 | 109 | 15 |
| Triglycerides (fasted) | 584 | 121 | 115 | -6 | 549 | 131 | 140 | 9 |
Subjects co-infected with hepatitis B and/or hepatitis C virus
In subjects co-infected with hepatitis B or C virus receiving Edurant, the incidence of hepatic enzyme elevation was higher than in subjects receiving Edurant who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.
Drug Interactions
[See also Contraindications (4) and Clinical Pharmacology (12.3).]
Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of Edurant and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Co-administration of Edurant and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of Edurant with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
Edurant at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Edurant and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Edurant are also included in Table 4.
| Concomitant Drug Class: Drug Name | Effect on Concentration of Rilpivirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
| ||
| HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| didanosine*† | ↔ rilpivirine ↔ didanosine | No dose adjustment is required when Edurant is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after Edurant (which should be administered with a meal). |
| HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| NNRTI (delavirdine) | ↑ rilpivirine ↔ delavirdine | It is not recommended to co-administer Edurant with delavirdine and other NNRTIs. |
| Other NNRTIs (efavirenz, etravirine, nevirapine) | ↓ rilpivirine ↔ other NNRTIs | |
| HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir) | ||
| darunavir/ritonavir*† | ↑ rilpivirine ↔ boosted darunavir | Concomitant use of Edurant with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when Edurant is co-administered with darunavir/ritonavir. |
| lopinavir/ritonavir*† | ↑ rilpivirine ↔ boosted lopinavir | Concomitant use of Edurant with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when Edurant is co-administered with lopinavir/ritonavir. |
| other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) | ↑ rilpivirine ↔ boosted PI | Concomitant use of Edurant with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Edurant is not expected to affect the plasma concentrations of co-administered PIs. |
| unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) | ↑ rilpivirine ↔ unboosted PI | Concomitant use of Edurant with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Edurant is not expected to affect the plasma concentrations of co-administered PIs. |
| Other Agents | ||
| Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) | ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) | The combination of Edurant and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after Edurant. |
| ↓ rilpivirine (concomitant intake) | ||
| Azole Antifungal Agents: fluconazole itraconazole ketoconazole*† posaconazole voriconazole | ↑ rilpivirine ↓ ketoconazole | Concomitant use of Edurant with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when Edurant is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with Edurant. |
| H2-Receptor Antagonists: cimetidine famotidine*† nizatidine ranitidine | ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) | The combination of Edurant and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after Edurant. |
| ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) | ||
| Macrolide antibiotics: clarithromycin, erythromycin, troleandomycin | ↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ troleandomycin | Concomitant use of Edurant with clarithromycin, erythromycin and troleandomycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
| Narcotic Analgesics: methadone* | ↓ R(-) methadone ↓ S(+) methadone | No dose adjustments are required when initiating co-administration of methadone with Edurant. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
In addition to the drugs included in Table 4, the interaction between Edurant and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, sildenafil and tenofovir disoproxil fumarate. No clinically relevant drug-drug interaction is expected when Edurant is co-administered with maraviroc, raltegravir, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. 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 electrocardiogram [see Clinical Pharmacology (12.2)]. Edurant should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
No adequate and well-controlled or pharmacokinetic studies of Edurant use in pregnant women have been conducted. Studies in animals have shown no evidence of relevant embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Edurant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to Edurant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Edurant.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Edurant did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of Edurant in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy.
Hepatic Impairment
No dose adjustment of Edurant is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Edurant has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].
Renal Impairment
No dose adjustment is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution and with increased monitoring for adverse effects, as rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].
Overdosage
There is no specific antidote for overdose with Edurant. Human experience of overdose with Edurant is limited. Treatment of overdose with Edurant consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance may be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.
Edurant Description
Edurant (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Edurant is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.
The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 • HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:
Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.
Each Edurant tablet also contains the inactive ingredients croscarmellose sodium, magnesium stearate, lactose monohydrate, povidone K30, polysorbate 20 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.
Edurant - Clinical Pharmacology
Mechanism of Action
Rilpivirine is an antiviral drug [see Clinical Pharmacology (12.4)].
Pharmacodynamics
Effects on Electrocardiogram
The effect of Edurant at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 4.8 (8.2) milliseconds (i.e., below the threshold of clinical concern).
When supratherapeutic doses of 75 mg once daily and 300 mg once daily of Edurant were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of Edurant 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of Edurant [see Warnings and Precautions (5.1)].
Pharmacokinetics
Pharmacokinetics in Adults
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
| Parameter | Rilpivirine 25 mg once daily N = 679 |
|---|---|
| AUC24h (ng∙h/mL) | |
| Mean ± Standard Deviation | 2397 ± 1032 |
| Median (Range) | 2204 (482 – 8601) |
| C0h (ng/mL) | |
| Mean ± Standard Deviation | 80 ± 37 |
| Median (Range) | 74 (1 – 300) |
Absorption and Bioavailability
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of Edurant is unknown.
Effects of Food on Oral Absorption
The exposure to rilpivirine was approximately 40% lower when Edurant was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When Edurant was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
Distribution
Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Metabolism
In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.
Elimination
The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.
Special Populations
Hepatic Impairment
Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Edurant has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.6)].
Hepatitis B and/or Hepatitis C Virus Co-infection
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
Renal Impairment
Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)].
Gender
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
Race
Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
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