View source for Rilpivirine

{{DrugProjectFormSinglePage
|authorTag={{AP}}
|genericName=Rilpivirine
|aOrAn=a
|drugClass=[[non-nucleoside reverse transcriptase inhibitor]] ([[NNRTI]])
|indicationType=treatment
|indication=[[human immunodeficiency virus type 1]] ([[HIV-1]]) infection in antiretroviral treatment-naïve adult patients with [[HIV-1]] [[RNA]] less than or equal to 100,000 copies/mL at the start of therapy
|adverseReactions=[[depressive disorders]], [[headache]], [[insomnia]] and [[rash]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Rilpivirine in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Rilpivirine in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Rilpivirine in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Rilpivirine in pediatric patients.
|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]]:
*the anticonvulsants [[carbamazepine]], [[oxcarbazepine]], [[phenobarbital]], [[phenytoin]]
*the antimycobacterials [[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=====Drug Interactions====
*Caution should be given to prescribing EDURANT with drugs that may reduce the exposure of rilpivirine. 
*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]]. 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) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among EDURANT (n = 686) or [[efavirenz]] (n = 682) was 9% and 8%, 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. [[Suicidal]] ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the EDURANT 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.

====Hepatotoxicity====
*Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying [[hepatitis B]] or [[hepatitis C]], or marked elevations in [[transaminases]] prior to treatment may be at increased risk for worsening or development of [[transaminase]] elevations with use of EDURANT. A few cases of hepatic toxicity have been reported in 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 is recommended in patients with underlying hepatic disease such as [[hepatitis B]] or [[hepatitis C]], 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.

====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 infection]], [[cytomegalovirus]], [[Pneumocystis jiroveci pneumonia]] or [[tuberculosis]]), which may necessitate further evaluation and treatment.
*Autoimmune disorders (such as [[Graves' disease]], [[polymyositis]], and [[Guillain-Barré syndrome]]) have also been reported to occur in the setting of [[immune reconstitution syndrome]]; however, the time to onset is more variable, and can occur many months after initiation of treatment.
|drugInteractions=*Rilpivirine is primarily metabolized by [[cytochrome P450]] [[CYP3A]], 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.


[[file:Rilpivirine DI.png|none|400px]]

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: [[acetaminophen]], [[atorvastatin]], [[chlorzoxazone]], [[ethinylestradiol]], [[norethindrone]], [[raltegravir]], [[sildenafil]], [[telaprevir]] 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 is co-administered with [[maraviroc]], [[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]].  EDURANT should be used with caution when co-administered with a drug with a known risk of [[Torsade de Pointes]].
|FDAPregCat=B
|useInPregnancyFDA=*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.
|useInNursing=*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.
|useInPed=*Safety and effectiveness in pediatric patients have not been established.
|useInGeri=*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.
|useInRenalImpair=*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.
|useInHepaticImpair=*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).
|overdose=*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. *Administration of [[activated charcoal]] may 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.
|drugBox={{drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 417509820
| IUPAC_name = 4-{[4-({4-[(''E'')-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
| image = Rilpivirine structure1.png
| width = 180px

<!--Clinical data-->
| tradename = Edurant
| Drugs.com = {{drugs.com|CDI|rilpivirine}}
| MedlinePlus = a611037
| licence_US = Rilpivirine
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = B
| pregnancy_category =  
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!--             / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL         / P       / POM / CD / Class A, B, C -->
| legal_US = Rx-only
| legal_status =  
| routes_of_administration = Oral

<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound =  
| metabolism =  
| elimination_half-life = 38 hours
| excretion =  

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 500287-72-9
| ATC_prefix = J05
| ATC_suffix = AG05
| PubChem = 6451164
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 68606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =  
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 4953643
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 175691
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = FI96A8X663
| NIAID_ChemDB = 169030
| PDB_ligand = T27

<!--Chemical data-->
| C=22 | H=18 | N=6
| molecular_weight = 366.42 g/mol
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = YIBOMRUWOWDFLG-ONEGZZNKSA-N
}}
|mechAction=Rilpivirine is a diarylpyrimidine [[non-nucleoside reverse transcriptase inhibitor]] ([[NNRTI]]) of [[human immunodeficiency virus type 1]] ([[HIV-1]]) and inhibits [[HIV-1]] replication by non-competitive inhibition of [[HIV-1 reverse transcriptase]] ([[RT]]). Rilpivirine does not inhibit the human cellular [[DNA polymerases]] α, β and γ.
|PD=====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 2.0 (5.0) 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.
|PK====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.

[[file:Rilpivirine PK1.png|none|300px]]

====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]] [[CYP3A]] 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.

====Pediatric Patients====
*The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established [see USE IN SPECIFIC POPULATIONS (8.4)].

====Drug Interactions====
*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. 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 and to the class of NNRTIs.
*EDURANT at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
*Drug interaction studies were performed with EDURANT and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other drugs on EDURANT). The effect of co-administration of EDURANT on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see DRUG INTERACTIONS (7).]
|alcohol=Alcohol-Rilpivirine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}
__NOTOC__
{{Rilpivirine}}
{{CMG}}; {{AE}} {{chetan}}

==Overview==
'''Rilpivirine''' (TMC278) is a [[diarylpyrimidine]] under under investigation as a treatment for [[HIV]] infection.  It is a [[non-nucleoside reverse transcriptase inhibitor]] with many times the potency of current available agents in that class, such as [[efavirenz]].<ref>{{cite journal |author=Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B |title=Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects |journal=AIDS |volume=20 |issue=13 |pages=1721–6 |year=2006 |pmid=16931936 |doi=10.1097/01.aids.0000242818.65215.bd |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00002030-200608220-00005}}</ref><ref>Pozniak A, Morales-Ramirez J, Mohap L et al. [http://www.retroconference.org/2007/Abstracts/30659.htm 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients.] Oral abstract 144LB.
</ref>It is expected to be [[FDA]] approved as soon as 2009.<ref>Steve Mitchell. [http://www.terradaily.com/reports/HIV_Market_To_Top_10_Billion_Dollars_999.html HIV Market To Top 10 Billion Dollars]. United Press International. April 11, 2007.</ref>

==Category==
Antiretroviral
==US Brand Names==
Edurant<sup>®</sup>

==FDA Package Insert==

'''  [[Rilpivirine description|Description]]'''
'''| [[Rilpivirine clinical pharmacology|Clinical Pharmacology]]'''
'''| [[Rilpivirine microbiology|Microbiology]]'''
'''| [[Rilpivirine indications and usage|Indications and Usage]]'''
'''| [[Rilpivirine contraindications|Contraindications]]'''
'''| [[Rilpivirine warnings and precautions|Warnings and Precautions]]'''
'''| [[Rilpivirine adverse reactions|Adverse Reactions]]'''
'''| [[Rilpivirine drug interactions|Drug Interactions]]'''
'''| [[Rilpivirine overdosage|Overdosage]]'''
'''| [[Rilpivirine clinical studies|Clinical Studies]]'''
'''| [[Rilpivirine dosage and administration|Dosage and Administration]]'''
'''| [[Rilpivirine how supplied|How Supplied]]'''
'''| [[Rilpivirine labels and packages|Labels and Packages]]'''

==Mechanism of Action==
A HIV-1 replication inhibitor acting by non-competitive inhibition of HIV-1 reverse transcriptase .  It is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1)
==References==
{{Reflist|2}}

[[Category:Antibiotics]]
[[Category:Wikinfect]]