Edurant Ped Drug Information
Generic name: RILPIVIRINE HYDROCHLORIDE
Uses of Edurant Ped
Treatment of HIV-1 in Treatment-Naïve Patients EDURANT and EDURANT PED, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 2 years of age and older and weighing at least 14 kg with plasma HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. Limitations of Use More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL.
Treatment of HIV-1 in Combination with Cabotegravir EDURANT is indicated in combination with VOCABRIA (cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as: oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension). oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).
Dosage & Administration of Edurant Ped
Overview of Different Dosage Forms EDURANT is available in two dosage forms: EDURANT 25 mg film-coated tablets for adults and pediatric patients weighing at least 25 kg. EDURANT PED 2.5 mg tablets for oral suspension should only be given to pediatric patients weighing at least 14 kg to less than 25 kg. Do not substitute EDURANT tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
Take EDURANT and EDURANT PED once daily with a meal in combination with other antiretrovirals.
Recommended Dosage in Treatment-Naïve Adult Patients
The recommended dosage of EDURANT in adult patients is one 25 mg tablet taken orally once daily with a meal.
Recommended Dosage in Treatment-Naïve Pediatric Patients 2 Years of Age and Older and Weighing at least 14 kg The recommended dosage of EDURANT and EDURANT PED in pediatric patients 2 years of age and older and weighing at least 14 kg is based on body weight (see Table 1 ). Both EDURANT and EDURANT PED should be taken orally once daily with a meal.
Preparation and Administration Instructions for EDURANT PED Only Advise patients or caregivers of patients taking EDURANT PED to refer to the Instructions for Use to properly prepare and take the medication. EDURANT PED must be dispersed in drinking water and taken immediately with a meal. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared.
The patient should not chew or swallow EDURANT PED whole. The following instructions should be followed: Place the tablets for oral suspension in a cup, add 5 mL (1 teaspoon) of drinking water at room temperature. Do not crush the tablets.
Swirl the cup carefully for 1–2 minutes to disperse the tablets. The oral suspension will start to look cloudy. Take all the prepared oral suspension immediately or to aid in administration, the oral suspension can be further diluted with 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce.
Swirl and take all the medicine immediately. A spoon can be used if needed. Make sure the entire dose is taken and no medicine is left in the cup.
If required, add another 5 mL (1 teaspoon) of drinking water (or alternative beverage or soft food), swirl and drink immediately.
Recommended Dosage During Pregnancy
Refer to Table 1 for dosing recommendations for pediatric patients. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely.
Recommended Dosage with Rifabutin Coadministration If EDURANT is coadministered with rifabutin, the EDURANT dose should be increased to 50 mg (two 25 mg tablets) once daily, taken with a meal. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal. Note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated.
Refer to CABENUVA labeling for additional detail.
| Body Weight (kg) | EDURANT 25 mg Tablets | EDURANT PED 2.5 mg Tablets for Oral Suspension | Total Daily Dose |
|---|---|---|---|
| 14 kg to less than 20 kg | Not recommended | 5 tablets once daily | 12.5 mg EDURANT PED once daily |
| 20 kg to less than 25 kg | Not recommended | 6 tablets once daily | 15 mg EDURANT PED once daily |
| Greater than or equal to 25 kg | 1 tablet once daily | Not recommended | 25 mg EDURANT once daily |
Side Effects of Edurant Ped
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. Clinical Trials Experience in Adults The safety assessment is based on the Week 96 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). The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 104.3 and 104.1 weeks, respectively.
Most adverse reactions occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to adverse reaction, regardless of severity, was 2% and 4%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 10 subjects in the efavirenz arm.
Common Adverse Reactions Adverse reactions of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Table 3: Selected Adverse Reactions of at Least Moderate Intensity Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). (Grades 2–4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects No new adverse reaction terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks.
The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks. Less Common Adverse Reactions Adverse reactions of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving EDURANT are listed below by System Organ Class. Some adverse 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 Disorders: somnolence Psychiatric Disorders: sleep disorders, anxiety Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis Laboratory Abnormalities in Treatment-Naïve Subjects The percentage of subjects treated with EDURANT or efavirenz in the Phase 3 trials with selected laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 4. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, fourteen subjects in the EDURANT group and nine subjects in the efavirenz group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the EDURANT group is not known. Serum Creatinine In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with EDURANT. 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. Serum creatinine increases occurred regardless of the background N(t)RTI regimen. Serum Lipids Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 5.
The clinical benefit of these findings has not been demonstrated. Table 5: Lipid Values, Mean Change from Baseline Excludes subjects who received lipid lowering agents during the treatment period 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. Use in Combination with Cabotegravir Safety findings from Phase 3/3b trials in adults were similar when EDURANT was administered in combination with VOCABRIA (cabotegravir) or other antiretrovirals. See full prescribing information for VOCABRIA and CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for additional information.
The median duration of exposure was 63.5 weeks. There were no patients who discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.
Adverse reactions were reported in nineteen pediatric subjects (53%). Most adverse reactions were Grade 1 or 2. Observed laboratory abnormalities were comparable to those in adults.
Adrenal Function In trial TMC278-C213 Cohort 1, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 micrograms/dL. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Trial 208580 Based on data from the Week 16 analysis of the MOCHA trial in 15 adolescents (12 to less than 18 years of age and weighing ≥35 kg) receiving EDURANT (25 mg once daily) in addition to continuing background antiretroviral therapy, the safety profile during the oral lead-in period in adolescents was consistent with the safety profile established with EDURANT in adults.
A total of 18 and 26 pediatric subjects were enrolled in Trial TMC278-C213 and Trial TMC278HTX2002, respectively. Overall, the safety data in these pediatric studies were similar to those observed in adults. Safety results from the two trials are summarized below.
All adverse reactions were Grade 1 or 2. Adverse reactions reported in at least 2 subjects, regardless of grading, in Trial TMC278-C213 Cohort 2 were: decreased appetite (3/18, ). No adverse reactions led to discontinuation.
Among the 13 subjects with low basal cortisol pre-dose at baseline, 2 subjects had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with rilpivirine. For both subjects, no adverse events suggestive for adrenal insufficiency were reported. The remaining 11 subjects had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment.
In 4 subjects, the serum cortisol levels remained low after repeat serum basal cortisol testing or after ACTH stimulation testing. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and Genitourinary Disorders: nephrotic syndrome Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
| System Organ Class, Preferred Term, % | Pooled Data from the Phase 3 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 | ||
| Abdominal pain | 2% | 2% |
| Nausea | 1% | 3% |
| Vomiting | 1% | 2% |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 2% | 2% |
| Nervous System Disorders | ||
| Headache | 3% | 4% |
| Dizziness | 1% | 7% |
| Psychiatric Disorders | ||
| Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. | 5% | 4% |
| Insomnia | 3% | 4% |
| Abnormal dreams | 2% | 4% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 3% | 11% |
| Laboratory Parameter Abnormality, (%) | DAIDS Toxicity Range | Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials | |
|---|---|---|---|
| EDURANT + BR N=686 | Efavirenz + BR N=682 | ||
| BIOCHEMISTRY | |||
| 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. | |||
| Increased Creatinine | |||
| Grade 1 | ≥1.1–≤1.3 × ULN | 6% | 1% |
| Grade 2 | >1.3–≤1.8 × ULN | 1% | 1% |
| Grade 3 | >1.8–≤3.4 × ULN | <1% | 0 |
| Grade 4 | >3.4 × ULN | 0 | <1% |
| Increased AST | |||
| Grade 1 | ≥1.25–≤2.5 × ULN | 16% | 19% |
| Grade 2 | >2.5–≤5.0 × ULN | 4% | 7% |
| 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 | 18% | 20% |
| Grade 2 | >2.5–≤5.0 × ULN | 5% | 7% |
| 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 | 3% | 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 | 17% | 31% |
| Grade 2 | 6.20–7.77 mmol/L 240–300 mg/dL | 7% | 19% |
| Grade 3 | >7.77 mmol/L >300 mg/dL | <1% | 3% |
| Increased LDL Cholesterol (fasted) | |||
| Grade 1 | 3.37–4.12 mmol/L 130–159 mg/dL | 14% | 26% |
| Grade 2 | 4.13–4.90 mmol/L 160–190 mg/dL | 5% | 13% |
| Grade 3 | ≥4.91 mmol/L ≥191 mg/dL | 1% | 5% |
| 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% | 3% |
| Grade 4 | >13.56 mmol/L >1,200 mg/dL | 0 | 1% |
| Pooled Data from the Week 96 Analysis of the Phase 3 TMC278-C209 and TMC278-C215 Trials | ||||||||
|---|---|---|---|---|---|---|---|---|
| EDURANT + BR | Efavirenz + BR | |||||||
| N | Baseline | Week 96 | N | Baseline | Week 96 | |||
| Mean (95% CI) | Mean (mg/dL) | Mean (mg/dL) | Mean Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values (mg/dL) | Mean (mg/dL) | Mean (mg/dL) | Mean Change (mg/dL) | ||
| N=number of subjects per treatment group; BR=background regimen | ||||||||
| Total Cholesterol (fasted) | 546 | 161 | 166 | 5 | 507 | 160 | 187 | 28 |
| HDL-cholesterol (fasted) | 545 | 41 | 46 | 4 | 505 | 40 | 51 | 11 |
| LDL-cholesterol (fasted) | 543 | 96 | 98 | 1 | 503 | 95 | 109 | 14 |
| Triglycerides (fasted) | 546 | 122 | 116 | -6 | 507 | 130 | 141 | 11 |
Warnings & Cautions for Edurant Ped
Skin and Hypersensitivity Reactions
Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT.
No Grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy. Discontinue EDURANT or EDURANT PED immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia.
Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.
Hepatotoxicity
Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT or EDURANT PED. A few cases of hepatic toxicity have been reported in adult patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors.
Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with EDURANT or EDURANT PED is recommended in patients with underlying hepatic disease such as hepatitis B or C virus infection, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
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. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to EDURANT or EDURANT PED, and if so, to determine whether the risks of continued therapy outweigh the benefits. 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. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the EDURANT arm.
None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of EDURANT or EDURANT PED and other drugs may result in potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of EDURANT or EDURANT PED and possible development of resistance. Consider alternatives to EDURANT or EDURANT PED when coadministered with a drug that is known to have a risk of torsade de pointes. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.
Consider the potential for drug interactions prior to and during EDURANT or EDURANT PED therapy and review concomitant medications during therapy.
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 infection, cytomegalovirus, Pneumocystis jirovecii pneumonia or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Different Formulations Are Not Substitutable EDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. When a pediatric patient weighs 25 kg or greater, they must switch from EDURANT PED tablets for oral suspension to one 25 mg EDURANT tablet daily. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to rilpivirine.
Drug Interactions with Edurant Ped
Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT or EDURANT PED 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. Coadministration of EDURANT or EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
EDURANT or EDURANT PED at the recommended doses are not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT or EDURANT PED and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with EDURANT or EDURANT PED are also included in Table 6.
Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Coadministration is contraindicated with EDURANT or EDURANT PED. Antimycobacterials: rifampin rifapentine ↓ rilpivirine Coadministration is contraindicated with EDURANT or EDURANT PED. Coadministration is contraindicated with EDURANT or EDURANT PED.
Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes. Narcotic Analgesics: methadone ↓ R(-) methadone ↓ S(+) methadone No dose adjustments are required when initiating coadministration of methadone with EDURANT or EDURANT PED. Proton Pump Inhibitors: e.g., esomeprazole lansoprazole omeprazole pantoprazole rabeprazole ↓ rilpivirine Coadministration is contraindicated with EDURANT or EDURANT PED.
In addition to the drugs included in Table 6, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug: acetaminophen, atorvastatin, chlorzoxazone, cabotegravir, ethinylestradiol, norethindrone, raltegravir, sildenafil, simeprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when EDURANT or EDURANT PED is coadministered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
Consider alternatives to EDURANT or EDURANT PED when coadministered with drugs with a known risk of torsade de pointes. EDURANT and EDURANT PED should not be used in combination with NNRTIs. Coadministration of EDURANT or EDURANT PED with drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine.
Coadministration of EDURANT or EDURANT PED with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine. Refer to the Full Prescribing Information for other drugs that should not be coadministered with EDURANT or EDURANT PED and for other drugs that may require a change in dose or regimen. 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, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram.
| Concomitant Drug Class: Drug Name | Effect on Concentration of Rilpivirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑=increase, ↓=decrease, ↔=no change | ||
| 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 or EDURANT PED and antacids should be used with caution as coadministration 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 or EDURANT PED. |
| ↓ rilpivirine (concomitant intake) | ||
| Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ]. |
| Antimycobacterials: rifampin rifapentine | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ]. |
| Antimycobacterials: rifabutin The interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. | ↓ rilpivirine | Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout coadministration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily. |
| Azole Antifungal Agents: fluconazole itraconazole ketoconazole This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended doses of EDURANT once daily. posaconazole voriconazole | ↑ rilpivirine ↓ ketoconazole | Concomitant use of EDURANT or EDURANT PED 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 or EDURANT PED is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with EDURANT or EDURANT PED. |
| Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ]. |
| H 2 -Receptor Antagonists: cimetidine famotidine nizatidine ranitidine | ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) | The combination of EDURANT or EDURANT PED and H 2 -receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H 2 -receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT or EDURANT PED. |
| ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) | ||
| Herbal Products: St. John's wort ( Hypericum perforatum ) | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ]. |
| HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| NNRTI (delavirdine) | ↑ rilpivirine ↔ delavirdine | It is not recommended to coadminister EDURANT or EDURANT PED with delavirdine and other NNRTIs. |
| Other NNRTIs (efavirenz, etravirine, nevirapine) | ↓ rilpivirine ↔ other NNRTIs | |
| HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| didanosine | ↔ rilpivirine ↔ didanosine | No dose adjustment is required when EDURANT or EDURANT PED is coadministered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT or EDURANT PED (which should be administered with a meal). |
| HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir) | ||
| darunavir/ritonavir | ↑ rilpivirine ↔ boosted darunavir | Concomitant use of EDURANT or EDURANT PED with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT or EDURANT PED is coadministered with darunavir/ritonavir. |
| Lopinavir/ritonavir | ↑ rilpivirine ↔ boosted lopinavir | Concomitant use of EDURANT or EDURANT PED with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT or EDURANT PED is coadministered with lopinavir/ritonavir. |
| Other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) | ↑ rilpivirine ↔ boosted PI | Concomitant use of EDURANT or EDURANT PED with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT or EDURANT PED is not expected to affect the plasma concentrations of coadministered PIs. |
| Unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) | ↑ rilpivirine ↔ unboosted PI | Concomitant use of EDURANT or EDURANT PED with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT or EDURANT PED is not expected to affect the plasma concentrations of coadministered PIs. |
| Macrolide or ketolide antibiotics: azithromycin clarithromycin erythromycin | ↑ rilpivirine ↔ azithromycin ↔ clarithromycin ↔ erythromycin | Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [Warnings and Precautions (5.4)]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. |
| Narcotic Analgesics: methadone | ↓ R(-) methadone ↓ S(+) methadone | No dose adjustments are required when initiating coadministration of methadone with EDURANT or EDURANT PED. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
| Proton Pump Inhibitors: e.g., esomeprazole lansoprazole omeprazole pantoprazole rabeprazole | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ]. |
Pregnancy Safety for Edurant Ped
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data ).
The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.
Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data ).
In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans (≥12 years of age and weighing at least 32 kg) at the recommended dose of 25 mg once daily (see Data ). Clinical Considerations Dosing During Pregnancy and the Postpartum Period Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required for pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely.
Data Human Data Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens. Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum.
Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period.
One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum.
All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV–1-infected adults.
No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg daily.
Pediatric Use of Edurant Ped
Pediatric Use The safety and effectiveness of EDURANT and EDURANT PED has been established for the treatment of HIV-1 infection in treatment-naïve pediatric patients 2 years of age and older and weighing at least 14 kg. Use of EDURANT or EDURANT PED in this population is supported by three trials: TMC278-C213, TMC278HTX2002 and MOCHA. Trial TMC278-C213 TMC278-C213 was a single arm, open-label, Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects, and was divided into two Cohorts.
Trial TMC278HTX2002 supports the safety and effectiveness of EDURANT and EDURANT PED in treatment-naïve HIV-1 infected pediatric patients 2 to less than 6 years of age. MOCHA Trial (NCT03497676) The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non- comparative study, MOCHA (IMPAACT 2017). Refer to the VOCABRIA and CABENUVA prescribing information for additional information when EDURANT is used in combination with cabotegravir.
The safety and effectivness of EDURANT in these pediatric subjects were similar to that seen in adults, and there were no significant changes on rilpivirine exposures. Safety and effectiveness in pediatric patients less than 2 years of age or weighing less than 14 kg have not been established. Treatment with EDURANT PED is not recommended in pediatric patients less than 2 years of age or weighing below 14 kg.
Contraindications for Edurant Ped
EDURANT and EDURANT PED are contraindicated for coadministration with the drugs in Table 2 for which 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 EDURANT PED or to the class of NNRTIs. Table 2: Drugs That are Contraindicated with EDURANT and EDURANT PED Drug Class Contraindicated Drugs in Class Clinical Comment Anticonvulsants Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. Antimycobacterials Rifampin Rifapentine Glucocorticoid (systemic) Dexamethasone (more than a single-dose treatment) Herbal Products St.
John's wort ( Hypericum perforatum ) Proton Pump Inhibitors e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. Coadministration of EDURANT or EDURANT PED is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance.
Overdosage Information for Edurant Ped
There is no specific antidote for overdose with EDURANT or EDURANT PED. Human experience of overdose with EDURANT or EDURANT PED is limited. Treatment of overdose with EDURANT or EDURANT PED 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.
It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.
Clinical Studies of Edurant Ped
Treatment-Naïve Adult Subjects
The evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated substitutions (RASs). The Phase 3 trials were identical in design, apart from the background regimen (BR).
In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load.
In TMC278-C215, randomization was also stratified by N(t)RTI BR. In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 14 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.
Table 14: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis) Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 15. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm 3 experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm 3. Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily.
Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received ≤2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RASs. At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA <50 copies/mL compared to 57% (51/89) of subjects in the control group.
Virologically-Suppressed Adults Treated in Combination with Cabotegravir The use of EDURANT in combination with VOCABRIA (cabotegravir) as an oral lead-in and in patients who miss planned injections with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) was evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR, Trial 201585: ATLAS ), and one Phase 3b randomized, multicenter, parallel-group, open-label, non-inferiority trial (Trial 207966: ATLAS-2M ) in subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL). See full prescribing information for VOCABRIA and CABENUVA for additional information.
Treatment-Naïve Pediatric Subjects (≥12 to less than 18 Years of Age) The pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected background regimen (BR) containing two NRTIs, was evaluated in trial TMC278-C213 Cohort 1, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg. Thirty six subjects were enrolled in the trial to complete at least 48 weeks of treatment. In the efficacy analysis, most subjects (75%; 28/36) had baseline HIV RNA <100,000 copies/mL.
The viral load for these 2 subjects was <50 copies/mL, post-Week 48. The mean increase (SE) in CD4+ from baseline was 215.9 cells/µL at Week 48. The safety and efficacy of EDURANT and EDURANT PED in treatment naïve pediatric subjects 2 to less than 6 years of age is supported by evidence from adequate and well-controlled studies of EDURANT in adults with additional population pharmacokinetic data from adults and pediatric subjects 6 years and older.
| Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials | ||
|---|---|---|
| EDURANT + BR N=686 | Efavirenz + BR N=682 | |
| BR=background regimen | ||
| Demographic Characteristics | ||
| Median Age, years (range) | 36 (18–78) | 36 (19–69) |
| Sex | ||
| Male | 76% | 76% |
| Female | 24% | 24% |
| Race | ||
| White | 61% | 60% |
| Black/African American | 24% | 23% |
| Asian | 11% | 14% |
| Other | 2% | 2% |
| Not allowed to ask per local regulations | 1% | 1% |
| Baseline Disease Characteristics | ||
| Median Baseline Plasma HIV-1 RNA (range), log 10 copies/mL | 5.0 (2–7) | 5.0 (3–7) |
| Percentage of Patients with Baseline Plasma Viral Load: | ||
| ≤100,000 | 54% | 48% |
| >100,000 to ≤500,000 | 36% | 40% |
| >500,000 | 10% | 12% |
| Median Baseline CD4+ Cell Count (range), cells/mm 3 | 249 (1–888) | 260 (1–1137) |
| Percentage of Subjects with: | ||
| Hepatitis B/C Virus Co-infection | 7% | 10% |
| Percentage of Patients with the Following Background Regimens: | ||
| tenofovir disoproxil fumarate plus emtricitabine | 80% | 80% |
| zidovudine plus lamivudine | 15% | 15% |
| abacavir plus lamivudine | 5% | 5% |
| EDURANT + BR N=686 | Efavirenz + BR N=682 | |
|---|---|---|
| N=total number of subjects per treatment group; BR=background regimen. | ||
| Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively. | ||
| HIV-1 RNA <50 copies/mL CI=Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96. | 76% | 77% |
| HIV-1 RNA ≥50 copies/mL Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. | 16% | 10% |
| No virologic data at Week 96 window Reasons | ||
| Discontinued study due to adverse event or death Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. | 4% | 8% |
| Discontinued study for other reasons and last available HIV-1 RNA <50 copies/mL (or missing) Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. | 4% | 5% |
| Missing data during window but on study | <1% | <1% |
| HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL) | ||
| ≤100,000 | 82% | 78% |
| >100,000 | 70% | 75% |
| HIV-1 RNA ≥50 copies/mL by Baseline HIV-1 RNA (copies/mL) | ||
| ≤100,000 | 9% | 8% |
| >100,000 | 24% | 11% |
| HIV-1 RNA <50 copies/mL by CD4+ cell count (cells/mm 3 ) | ||
| <200 | 68% | 74% |
| ≥200 | 81% | 77% |
| HIV-1 RNA ≥50 copies/mL by CD4+ cell count (cells/mm 3 ) | ||
| <200 | 27% | 10% |
| ≥200 | 10% | 9% |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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