Edurant^® (Tablets) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Janssen-Cilag S.p.A. (Italy)

Contact Information

JANSSEN, a pharmaceutical division of Johnson & Johnson LLC

ATC Code

J05AG05 (Rilpivirine)

Active Substance

Rilpivirine (Rec.INN registered by WHO)

Dosage Form

Edurant®

Film-coated tablets, 25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, round, biconvex, engraved with “TMC” on one side and “25” on the other side; the cross-section is from white to almost white.

Excipients: lactose monohydrate – 55.145 mg, microcrystalline cellulose – 16.605 mg, croscarmellose sodium – 6.05 mg, povidone K30 – 3.25 mg, magnesium stearate – 1.1 mg, polysorbate 20 – 0.35 mg.

Shell composition: hypromellose 2910 6 mPa.s – 1.76 mg, lactose monohydrate – 0.968 mg, macrogol 3000 – 0.352 mg, triacetin – 0.264 mg, titanium dioxide – 1.056 mg.

30 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; non-nucleoside reverse transcriptase inhibitors

Pharmacological Action

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1. The activity of rilpivirine is mediated by non-competitive inhibition of HIV-1 reverse transcriptase. Rilpivirine does not inhibit human cellular alpha-, beta-, gamma-DNA polymerases.

Antiviral activity in vitro

Rilpivirine is active against laboratory wild-type HIV-1 strains in acutely infected T-cell lines with a mean EC₅₀ for HIV-1/IIIB of 0.73 nM (0.27 ng/ml). Rilpivirine demonstrates limited activity against HIV-2 in vitro with EC₅₀ values from 2510 to 10830 nM (920-3970 ng/ml), however, due to the lack of clinical data, it is not recommended to prescribe Edurant^® for the treatment of HIV-2 infection.

Rilpivirine has antiviral activity against a wide range of group M HIV-1 representatives (subtypes A, B, C, D, E, F, G, H), for which its mean effective dose (EC₅₀) ranges from 0.07 to 1.01 nM (0.03-0.37 ng/ml), and primary group O isolates, for which its mean effective dose (EC₅₀) ranges from 2.88 to 8.45 nM (1.06-3.10 ng/ml).

Rilpivirine has additive antiviral activity in combination with nucleoside/nucleotide reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, stavudine, tenofovir), with protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir, and saquinavir), with non-nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, and nevirapine), as well as in combination with the fusion inhibitor enfuvirtide and the CCR5 co-receptor antagonist maraviroc. Rilpivirine produces a synergistic or additive antiviral effect in combination with the nucleoside reverse transcriptase inhibitors lamivudine and zidovudine, and the integrase inhibitor raltegravir.

Resistance

Cell culture

When selecting rilpivirine-resistant strains of wild-type HIV-1 of different origins and subtypes, as well as selecting HIV-1 strains resistant to NNRTIs, the following amino acid substitutions were most frequently encountered: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C, M230I.

The biological cutoff (BCO) for rilpivirine was determined at a fold change in EC₅₀ (FC) of 3.7, based on the analysis of susceptibility of a large number of clinical isolates and recombinant wild-type HIV-1 strains.

Treatment-naive patients

Amino acid substitutions associated with NNRTI resistance and most frequently encountered in such patients were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. However, in clinical trials, the presence of V90I and V189I substitutions at baseline did not affect the response to rilpivirine therapy. The E138K substitution emerged most frequently during rilpivirine therapy, usually in combination with the M184I substitution.

A larger number of patients with virologic failure on Edurant^® compared to patients with virologic failure on efavirenz developed resistance to lamivudine/emtricitabine.

Based on all available in vivo and in vitro data, the activity of rilpivirine is affected by the following amino acid substitutions present at baseline: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, H221Y, F227C, M230I, and M230L.

Cross-resistance

Mutant strains with HIV-1 resistance

Out of 67 laboratory recombinant HIV-1 strains with a single amino acid substitution in the reverse transcriptase gene, with a mutation resistant to NNRTIs, including the common K103N and Y181C, Rilpivirine demonstrated antiviral activity against 64 (96%) of these strains. It was shown that the presence of the K103N mutation alone does not lead to reduced susceptibility, whereas the combination of K103N and L100I mutations leads to a 7-fold reduction in susceptibility. Single amino acid substitutions associated with loss of susceptibility to rilpivirine were K101P, Y181I, and Y181V.

Recombinant strain isolates

Rilpivirine demonstrated susceptibility (FC < BCO) against 62% of 4786 recombinant strain isolates resistant to efavirenz and/or nevirapine.

HIV-1 infected treatment-naive patients.

According to clinical trial data, 31 out of 62 patients with virologic failure on Edurant^® and phenotypic resistance lost response to rilpivirine therapy. Moreover, 28 patients had resistance to etravirine, 27 to efavirenz, and 14 to nevirapine.

Effect on electrocardiogram parameters

The effect of Edurant^® on the QTcF interval when taken at the recommended dose of 25 mg once daily was studied in healthy volunteers. When taking Edurant^® at the recommended dose of 25 mg once daily, no clinically significant effect on the QTc interval was noted.

When studying the use of Edurant^® at doses exceeding therapeutic doses (75 mg once daily and 300 mg once daily) taken by healthy volunteers, the maximum mean and time-matched (upper bound of the 95% confidence interval) difference in QTcF interval values between the study drug and placebo after correction was 10.7 (15.3) and 23.3 (28.4) ms, respectively. At steady state, administration of the drug at doses of 75 mg once daily and 300 mg once daily led to an increase in the mean C_max in plasma by approximately 2.6 and 6.7 times, respectively, compared to the mean C_max observed at steady state with the administration of Edurant^® at the recommended dose of 25 mg once daily.

Pharmacokinetics

The pharmacokinetic properties of rilpivirine were studied in adult healthy volunteers and adult HIV-1-infected treatment-naive patients. The exposure of rilpivirine in HIV-1-infected patients was lower than in healthy volunteers.

Absorption

After oral administration, the C_max of rilpivirine in plasma is reached within 4-5 hours. The absolute bioavailability of rilpivirine is unknown.

Exposure to rilpivirine was approximately 40% lower when the drug was taken on an empty stomach compared to simultaneous administration with a normal-calorie meal (533 kcal) or a high-fat meal (928 kcal). When Edurant^® was taken with a protein-enriched beverage, drug exposure was 50% lower than when taken simultaneously with food.

Distribution

In vitro, 99.7% of rilpivirine is bound to plasma proteins, primarily albumin. The distribution of rilpivirine in biological fluids (cerebrospinal fluid, genital tract secretions) has not been studied.

Metabolism

In vitro studies have shown that Rilpivirine undergoes oxidative metabolism mediated by the cytochrome P450 (CYP)3A system.

Elimination

The terminal T_1/2 of rilpivirine is approximately 45 hours. After oral administration of a single dose of ¹⁴C-rilpivirine, approximately 85% and 6.1% of the radiolabeled drug dose was found in feces and urine, respectively.

The amount of rilpivirine found unchanged in feces averaged 25% of the administered dose. Only a negligible amount of unchanged rilpivirine (less than 1% of the administered dose) was detected in urine.

Pharmacokinetics in special patient groups

The pharmacokinetics of rilpivirine in children is currently under study. Due to insufficient data on the drug in children, it is impossible to provide recommendations regarding the prescription of Edurant^® to children.

Pharmacokinetic analysis of data from HIV-1-infected patients showed that the pharmacokinetics of rilpivirine remains comparable for all age groups (from 18 to 78 years). Dose adjustment in elderly patients is not required.

No clinically significant differences in the pharmacokinetics of rilpivirine were found between men and women.

Pharmacokinetic analysis of data from HIV-1-infected patients showed that race does not affect the efficacy of Edurant^®.

Rilpivirine is metabolized and eliminated by the liver. In a study comparing pharmacokinetic parameters in patients with mild hepatic impairment (Child-Pugh class A) and control patients, as well as pharmacokinetic parameters in patients with moderate hepatic impairment (Child-Pugh class B) and control patients, the exposure of rilpivirine, taken in multiple doses, was 47% higher in patients with mild hepatic impairment, and 5% higher in patients with moderate hepatic impairment. In patients with mild or moderate hepatic impairment, dose adjustment is not required. The pharmacokinetics of Edurant^® in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Population pharmacokinetic analysis showed that hepatitis B and/or C virus co-infection did not have a clinically significant effect on rilpivirine exposure.

The pharmacokinetics of rilpivirine in patients with renal impairment has not been studied. A negligible amount of rilpivirine is excreted by the kidneys. The effect of renal impairment on the elimination of rilpivirine is considered minimal. It is unlikely that hemodialysis or peritoneal dialysis can significantly accelerate the elimination of rilpivirine from the body, since Rilpivirine has high affinity for plasma proteins.

Indications

• In combination with other antiretroviral drugs as first-line therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult patients.

ICD codes

Dosage Regimen

Treatment should be carried out by a physician experienced in the therapy of HIV infection. Edurant^® should be used only in combination with other antiretroviral agents. The recommended dose of the drug is 25 mg (1 tablet) orally once daily with a meal.

If a dose is delayed by less than 12 hours, the patient should take the Edurant^® tablet with food as soon as possible, and the next tablet should be taken at the usual time. If a dose is delayed by more than 12 hours, the missed dose should not be taken; the next tablet should be taken at the usual time.

Dose adjustment of Edurant^® in elderly patients is not required.

The efficacy and safety of Edurant^® in children under 18 years of age have not been established.

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), dose adjustment is not required. Data on the use of the drug in patients with severe hepatic impairment (Child-Pugh class C) are not available.

In patients with renal impairment, dose adjustment of Edurant^® is not required.

Adverse Reactions

In clinical trials, the most frequent adverse reactions were: depression, insomnia, headache, increased activity of hepatic transaminases, and rash.

Among severe adverse reactions were increased transaminase activity (1.6%), depression (0.7%), abdominal pain (0.4%), dizziness (0.3%), rash (0.3%).

Adverse reactions of the drug are systematized relative to each organ system depending on the frequency of occurrence, using the following classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated cases.

From the digestive system: common – decreased appetite, abdominal pain, vomiting, nausea; uncommon – abdominal discomfort.

From the CNS: common – depression, insomnia, abnormal dreams, sleep disorder, dizziness, headache; uncommon – depressed mood, somnolence.

From the skin and subcutaneous tissue: common – rash.

From laboratory parameters: common – increased transaminase activity. Cases of decreased hemoglobin concentration, platelets, leukocytes, increased activity of AST, ALT, pancreatic amylase, lipase, increased bilirubin content, total cholesterol, LDL and triglycerides were also observed. The mean change in concentration of total cholesterol (fasting) was 2 mg/dL, HDL (fasting) – 4 mg/dL, LDL (fasting) – 1 mg/dL and triglycerides (fasting) – 7 mg/dL.

General: common – fatigue.

Description of selected adverse reactions

Redistribution of subcutaneous adipose tissue (SAT)

Combined antiretroviral therapy causes redistribution of SAT (lipodystrophy) in HIV-infected patients and is manifested by loss of subcutaneous fat in the periphery (upper and lower limbs) and facial area, increase in adipose tissue in the intra-abdominal and visceral areas, breast hypertrophy, and accumulation of subcutaneous fat in the dorsocervical area (“buffalo hump”).

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency who have just started combined antiretroviral therapy, an inflammatory response to the presence of opportunistic agents may develop against the background of immune system recovery, with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome).

Patients co-infected with hepatitis B and/or C virus

In patients co-infected with hepatitis B or C virus who received Edurant^®, the frequency of elevated liver enzyme levels was higher than in patients with HIV infection alone. The pharmacokinetic exposure of rilpivirine in co-infected patients is comparable to that in patients without co-infection.

Serum creatinine level

An increase in serum creatinine was observed during the first four weeks of therapy and remained stable up to week 48. The mean change after 48 weeks of therapy was 0.09 mg/dL (range: from -0.20 mg/dL to 0.62 mg/dL). In patients with mild or moderate renal impairment, the observed increase in serum creatinine was comparable to the increase in serum creatinine concentration in patients with normal renal function. These changes were considered clinically insignificant, and no patient discontinued therapy due to increased serum creatinine levels.

Contraindications

• Children under 18 years of age (currently insufficient data on the safety and efficacy of Edurant^® in children under 18 years; therefore, until clinical data on safety and efficacy in children are obtained, the use of the drug in this category of patients is not recommended);
• Severe hepatic impairment (Child-Pugh class C (currently insufficient data on the safety and efficacy of Edurant^® in patients with severe hepatic impairment (Child-Pugh class C); therefore, until clinical data on safety and efficacy in patients with severe hepatic impairment (Child-Pugh class C) are obtained, the use of the drug in this category of patients is not recommended);
• Concomitant use with drugs that significantly reduce the plasma concentration of rilpivirine, as this may lead to loss of virologic response or development of resistance to Edurant^® or to the entire class of non-nucleoside reverse transcriptase inhibitors. A significant decrease in plasma concentrations of rilpivirine may occur when drugs taken concomitantly with Edurant^® are metabolized via the CYP3A isoenzyme or increase gastric pH: anticonvulsants – carbamazepine, oxcarbazepine, phenobarbital, phenytoin; antituberculosis drugs – rifabutin, rifampicin, rifapentine; proton pump inhibitors – such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; systemic glucocorticoids – dexamethasone (when taken more than once); preparations based on St. John’s wort (Hypericum perforatum);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• hypersensitivity to rilpivirine or any other components of the drug.

Edurant^® should be used with caution in combination with drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type. Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. A study in healthy volunteers found that Rilpivirine at high doses (75 mg once daily and 300 mg once daily) prolonged the QT interval on the ECG.

Use in Pregnancy and Lactation

No adequate and well-controlled clinical or pharmacokinetic studies have been conducted on the use of Edurant^® in pregnant women. Animal studies revealed no evidence of embryotoxicity or effects on reproductive function. Edurant^® should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

It is not known whether Rilpivirine passes into the breast milk of nursing women. Due to the risk of HIV transmission and the potential for adverse events in breastfed infants, breastfeeding is not recommended while taking the drug.

Due to the lack of adequate and well-controlled clinical studies on the use of Edurant^® in pregnant women, women of childbearing age are advised to use effective contraception during drug intake.

There are no data on the effect of rilpivirine on reproductive function.

Use in Hepatic Impairment

No dose adjustment of the drug is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Data on the use of the drug in patients with severe hepatic impairment (Child-Pugh class C) are not available.

Use in Renal Impairment

No dose adjustment of Edurant^® is required in patients with renal impairment.

Pediatric Use

Currently, there are insufficient data on the safety and efficacy of Edurant^® in children under 18 years of age. Therefore, until clinical data on safety and efficacy in children are obtained, the use of the drug in this patient category is not recommended.

Geriatric Use

No dose adjustment of Edurant^® is required in elderly patients.

Special Precautions

Patients should be informed that current antiretroviral therapy cannot cure HIV infection and cannot prevent the transmission of HIV through blood or sexual contact. Necessary precautions should be taken to prevent HIV transmission.

The following should be considered before initiating therapy with Edurant^®: in study participants receiving Edurant^® who had HIV-1 RNA greater than 100,000 copies/mL at the start of therapy, a lack of virological response was observed more frequently compared to patients who had HIV-1 RNA levels less than 100,000 copies at the start of therapy. The observed virological failure during treatment with Edurant^® led to a higher frequency of resistance development to NNRTI class drugs. In patients with observed virological failure receiving Edurant^® therapy, resistance to lamivudine/emtricitabine developed more frequently compared to patients with observed virological failure receiving efavirenz.

Drug Interactions

Caution should be exercised when prescribing Edurant^® in combination with other drugs that may reduce the therapeutic effect of rilpivirine.

Depressive Disorders

Cases of depressive disorders (mood swings, depression, dysphoria, major depression, behavioral instability, negative thoughts, suicidal ideation, suicide attempts) have been reported during treatment with Edurant^®. Most cases were mild to moderate in severity. If a patient experiences symptoms of moderate depression, the patient should immediately seek medical attention to determine whether these symptoms are related to Edurant^® use. If a causal relationship is established, the risk versus benefit of continuing therapy should be assessed.

Redistribution of Subcutaneous Adipose Tissue

Combination antiretroviral therapy may cause redistribution of subcutaneous adipose tissue (lipodystrophy) in HIV-infected patients. The exact mechanism and long-term consequences of this phenomenon are currently unknown. An association is suggested between the development of visceral lipomatosis and protease inhibitor use, and between lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs). An increased risk of developing lipodystrophy is associated with individual factors such as older age, as well as drug-related factors, such as a longer duration of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include an assessment of physical signs of subcutaneous fat redistribution.

Immune Reconstitution Syndrome

At the initiation of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to asymptomatic opportunistic agents, with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome), which may require further careful monitoring and treatment. Such reactions are usually observed within the first few weeks of starting treatment. Similar examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis pneumonia. Any inflammatory symptoms should be assessed and, if necessary, treated.

Effect on Driving and Operating Machinery

Edurant^® has no or negligible influence on the ability to drive and use machines.

Overdose

Data on human overdose with the drug are limited.

Symptoms of overdose may include headache, nausea, dizziness, and/or unusual dreams.

Treatment. There is no specific antidote. Treatment involves general supportive measures, including monitoring of vital signs and ECG (QT interval), as well as monitoring the patient’s clinical status. If indicated, gastric lavage may be performed to remove unabsorbed active substance. Administration of activated charcoal is also possible for this purpose. Since Rilpivirine is highly bound to plasma proteins, dialysis is ineffective in case of overdose.

Drug Interactions

Drugs Affecting the Metabolism of Rilpivirine

Rilpivirine is metabolized by cytochrome P450 (CYP)3A isoenzymes; therefore, drugs that induce or inhibit CYP3A affect the clearance of rilpivirine.

Concomitant use of Edurant^® and drugs that can induce CYP3A may lead to decreased plasma concentrations of rilpivirine and reduce the therapeutic effect of rilpivirine.

Concomitant use of Edurant^® with drugs that inhibit CYP3A may lead to increased plasma concentrations of rilpivirine.

Concomitant use of Edurant^® and drugs that increase gastric pH may lead to decreased plasma concentrations of rilpivirine and a possible reduction in the therapeutic effect of rilpivirine.

Effect of Rilpivirine on the Metabolism of Other Drugs

It is unlikely that Edurant^®, administered at a dose of 25 mg once daily, has a clinically significant effect on the clearance of drugs metabolized by cytochrome P450 isoenzymes.

Drug interactions of rilpivirine when co-administered with other drugs are presented in Table 1 (increase denoted by – ↑, decrease – ↓, no change – ↔, not applicable – NA, confidence interval – CI).

Table 1. Drug Interactions and Dosing Recommendations.

^*The interaction between Edurant^® and the drug was studied in a clinical trial. All other drug interactions are presumed.

^#This drug interaction study was performed with Edurant^® at a dose exceeding the recommended dose. Dosing recommendations refer to the recommended dose of Edurant^® 25 mg once daily.

Male and Female Contraception

The likelihood of reduced efficacy of oral contraceptives when co-administered with Edurant^® is low. No dose adjustment of estrogen- and/or progesterone-based contraceptives is required when co-administered with Edurant^®.

Drugs that Prolong the QT Interval

Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. A study in healthy volunteers found that Rilpivirine at high doses (75 mg once daily and 300 mg once daily) prolonged the QT interval on the ECG. Therefore, Edurant^® should be used with caution in combination with drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type.

Storage Conditions

The drug should be stored in the original packaging to protect it from direct sunlight, out of the reach of children, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.