Rilpivirine

366.43

366.42

FI96A8X663

DTXSID10198189

C76929

Slightly yellow crystalline powder|White to off-white powder

J05AG05|J - Antiinfectives for systemic use

2933599090

97.4

4.5

1.3±0.1 g/cm3

245 °C @ Solvent: Diisopropyl ether, Acetonitrile

634.1°C at 760 mmHg

337.3±34.3 °C

1.665

H2O: <0.1mg/mlReadily soluble in DSMO (> 50 mg/mL); moderately soluble in PEG 400 (40 mg/mL). Practically insoluble in water (20 mg/mL, pH 7.0)

Refrigerator

2.84X10-12 mm Hg at 25 deg C (est)

Henry's Law constant = 5.3X10-15 atm-cu m/mol at 25 °C (est)

5.6|pKa = 5.6

Hygroscopic and light sensitive|White to almost white powder. Practically insoluble in water /Rilpivirine hydrochloride/

P264, P270, P273, P280, P301+P312, P305+P351+P338, P330, P337+P313, P391, P501

H302

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rilpivirine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rilpivirine hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P273, P280, P301+P312, P305+P351+P338, P330, P337+P313, P391, and P501|Aggregated GHS information provided by 9 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Rilpivirine did not induce chromosomal damage in vivo. It did not show any effect on mating or fertility in animal studies. On the other hand, mice studies have result positive for the formation of hepatocellular neoplasms which can be rodent-specific.

Serum aminotransferase elevations occur in 25% or more of patients on rilpivirine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in 1% to 4% of patients. The rate of serum aminotransferase elevations during rilpivirine therapy is higher in patients who are coinfected with hepatitis B or C [~10% have values greater than 5 times ULN]. The product label for rilpivirine induces a warning about hepatotoxicity particularly in patients with HBV or HCV coinfection and recommends monitoring for liver test abnormalities. During the first several years of wide spread clinical use of rilpivirine, a single case report of liver injury was published. The case was marked by prominent elevations in serum ALT and AST without jaundice arising within days of starting therapy and resolving rapidly upon stopping (Case 1). There was no rash, eosinophilia or other prominent immunoallergic features which are typical of the liver injury associated with nevirapine and efavirenz. Thus, clinically apparent hepatotoxicity due to rilpivirine may occur but is rare.

Concomitant use of omeprazole and rilpivirine has resulted in decreased rilpivirine plasma concentrations and AUC. Concomitant use of other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.|Concomitant use of famotidine and rilpivirine has resulted in decreased rilpivirine plasma concentrations and area under the concentration-time curve (AUC). Concomitant use of other histamine H2-receptor antagonists (e.g., cimetidine, nizatidine, ranitidine) also may result in decreased rilpivirine plasma concentrations. Rilpivirine and histamine H2-receptor antagonists should be used concomitantly with caution; histamine H2-receptor antagonists should be administered at least 12 hours before or at least 4 hours after rilpivirine.|Potential pharmacokinetic interaction with antacids such as aluminum hydroxide, calcium carbonate, or magnesium hydroxide (decreased plasma rilpivirine concentrations). Antacids and rilpivirine should be used concomitantly with caution; antacids should be administered at least 2 hours before or at least 4 hours after rilpivirine.|Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A. Concomitant use with drugs that induce CYP3A may result in decreased plasma rilpivirine concentrations and may result in possible loss of virologic response and development of resistance to rilpivirine or the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. Concomitant use with drugs that inhibit CYP3A may result in increased plasma rilpivirine concentrations. When the recommended rilpivirine dosage (25 mg once daily) is used, it is unlikely to have clinically important effects on the pharmacokinetics of drugs that are metabolized by CYP isoenzymes.

Rilpivirine is highly protein-bound thus, >99% of its dose can be bound to plasma protein in a concentration-dependent manner. The most important plasma binding proteins is albumin.

Rilpivirine, in combination with other agents, is indicated for the treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL and CD4+ cell count >200 cells/mm3. The FDA combination therapy approval of rilpivirine and dolutegravir is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.|FDA Label|Edurant, in combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in antiretroviral treatment‑naïve patients 12 years of age and older with a viral load ≤ 100,000 HIV‑1 RNA copies/ml.As with other antiretroviral medicinal products, genotypic resistance testing should guide the use of Edurant.|Treatment of human immunodeficiency virus (HIV-1) infection|Rekambys is indicated, in combination with cabotegravir injection, for the treatment of human immunodeficiency virus type 1 (HIV 1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class.

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used in combination with other antiretroviral agents in the therapy of human immunodeficiency virus (HIV) infection. Rilpivirine is associated with a low rate of transient serum aminotransferase elevations during therapy and has been implicated in rare cases of clinically apparent acute liver injury.

Antiviral Agents

HIV Reverse Transcriptase/antagonists & inhibitors|Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>/= 3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.

Adverse effects of moderate or severe intensity and reported in 2% or more of patients receiving rilpivirine include depressive disorders, insomnia, headache, and rash. Increased serum AST and/or ALT concentrations (more than 2.5 times the upper limit of normal (ULN) were reported in 3-4% of patients receiving rilpivirine.|Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease since concentrations of the drug may be increased due to alterations in absorption, distribution, or metabolism.|Rilpivirine and the fixed combination containing rilpivirine, emtricitabine, and tenofovir (Complera) have not been studied in patients with severe hepatic impairment (Child-Pugh class C).|Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic and/or renal function and potential for concomitant disease and drug therapy.|For more Drug Warnings (Complete) data for Rilpivirine (13 total), please visit the HSDB record page.

Ripivirine treatment produces a significant and effective reduction in the viral load based on the study of HIV-1 RNA copies per ml or immunologic changes by the determination of counts of CD4+ and CD8+ cells. The combinantion therapy (ripivirine and dolutegravir) presented the same viral supression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)|Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

Absorption of rilpivirine is characterized by a lag time followed by a linear increase in plasma concentration. Under fasting conditions, the Cmax of rilpivirine can be decreased even by 46% while its AUC can be reduced by 43%. When given with a protein-rich drink the Cmax and AUC of rilpivirine is decreased by 50%. Therefore, it is recommended to consume rilpiviridine with a non-protein-rich meal. The average Tmax of various rilpivirine concentrations is 3-4 h. The reported AUC in patients from clinical studies is 2235 ng h/ml.|Excreted fecally (85%, 25% as unchanged drug) and urine (6%, < 1% as unchanged drug).|In VIH-1 patients, the apparent volume of distribution in the central compartment was determined to be 152-173 L.|In HIV-1 patients, the apparent oral clearance is estimated to be 10.5-11.8 L/h.|After a single oral dose, an average of 85% of the dose is eliminated in feces (75% as metabolites) and 6% is eliminated in urine (only trace amounts as unchanged rilpivirine).|It is not known whether rilpivirine is distributed into human milk; however, the drug is distributed into milk in rats.

Mainly hepatically metabolized by CYP3A. Because it is highly protein bound, its free plasma concentration is very small thus is unlikely to inhibit cytochrome proteins to a clinically relevant degree despite being an inhibitor of CYP3A4, CYP2C19, and CYP2B6.|Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.

Plasma drug elimination is really slow, giving rilpivirine a half-life of 34-55 hours after oral administration.|The terminal elimination half-life of rilpivirine is approximately 50 hours.

Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ. Rilpivirine binds to the HIV-1 reverse transcriptase (RT) and its flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket.|Rilpivirine, a diarylpyrimidine nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Diarylpyrimidine NNRTIs (e.g., rilpivirine, etravirine) are capable of adapting to mutations in HIV-1 reverse transcriptase because of structural flexibility that allows for binding to the allosteric NNRTI binding pocket in a variety of conformations. Unlike other currently available NNRTIs, rilpivirine contains a cyanovinyl group that contributes to potency and maintains the drug's binding ability, despite the emergence of some resistance mutations.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Adverse effects of moderate or severe intensity and reported in 2% or more of patients receiving rilpivirine include depressive disorders, insomnia, headache, and rash. Increased serum AST and/or ALT concentrations (more than 2.5 times the upper limit of normal (ULN) were reported in 3-4% of patients receiving rilpivirine.|/SIGNS AND SYMPTOMS/ During phase 3 studies (ECHO and THRIVE studies), 8% of patients receiving rilpivirine reported depressive disorders compared to 6% of patients receiving efavirenz. While most depressive events were reported to be mild or moderate in severity, 1% of patients in each treatment group reported a grade 3 or 4 depressive disorder and 1% of patients in each treatment group discontinued therapy as a result of a depressive disorder.

278, TMC

Oral: Tablets, film-coated: 25 mg (of rilpivirine) with Emtricitabine 200 mg and Tenofovir Disoproxil Fumarate 300 mg, Complera (Gilead). /Rilpivirine combinations/|Oral: tablets, film-coated: 25 mg (of rilpivirine), Edurant (Janssen). /Rilpivirine hydrochloride/

Human drugs -> Edurant -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human drugs -> Rekambys -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients