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FORMULATION(s)

Fabricant : Gilead

DOSAGE

Adult dosage

1 tablet DIE with a meal to obtain optimal absorption of rilpivirine.
(See also the pharmacokinetics section)

For missed doses, the product monograph recommends an interval of 12 hours. Take the missed dose with a meal as soon as possible, unless there are only 18 hours or less before the next dose. Do not double the dose.

If patient vomits less than 4 hours after taking Odefsey®, the product monograph recommends taking a tablet with a meal. If vomiting occurs more than 4 hours after taking Odefsey®, he does not have to take another dose and must continue on usual schedule.

Pediatric dosage

Child or adolescent ≥ 35 kg : 1 tablet DIE with a meal.

Safety and efficacy have not been established in pediatric population < 35 kg.

Adjustment in renal impairment

CrCl ≥ 30 mL/min :  No adjustment required

CrCl < 30 mL/min and ≥ 15 mL/min : Administration not recommended

Adjustment in hepatic impairment

Child-Pugh A or B : No adjustment required

Child-Pugh C : Administration not recommended (not studied in this population)

COMPARATIVE EFFICIENCY

Studies in patients who have never received antiretrovirals

Dosage regimens containing rilpivirine

Clinical studies with Odefsey® have shown that :

  • Patients treated with a CD4+ cell count < 200 cells/µL had a greater number of virologic failures compared to patients with a CD4+ cell count ≥ 200 cells/µL.
  • Subjects treated with rilpivirine had a higher rate of overall resistance to NNRTIs compared to control (efavirenz). In addition, subjects treated with rilpivirine developed greater resistance associated with tenofovir and lamivudine/emtricitabine compared to control.

The safety and efficacy of Odefsey® have not been established in patients with a history of virologic failure.

Study

Comparator groups

Efficacy results (reaching a viral load < 50 copies/mL)

ECHO

RPV + FTC/TDF (N=346) vs EFV + FTC/TDF (N=344)

Week 48
ITT TAPRV*
Noninferiority of RPV + FTC/TDF (83% vs 83%, 95% CI -5.9 to 5.2)

THRIVE

RPV + FTC/TDF (N=340) vs EFV + FTC/TDF (N=338)

Week 48
Noninferiority of RPV + FTC/TDF (86% vs 82%, 95% CI -1.7 to 8.8)
P <0.0001

ECHO + THRIVE
(Analysis for patients with a VL < 100 000 copies/ml)

RPV + FTC/TDF (N=288) vs EFV + FTC/TDF (N=255)

Week 96
ITT TBLVR*
Noninferiority of RPV + FTC/TDF (84% vs 81%, 95% CI -3.6% to 9.3%)
SNAPSHOT Analysis
Noninferiority of RPV + FTC/TDF (83% vs 80%, 95% CI -3.6% to 9.1%)

*ITT TBLVR : Intent to Treat – Time before loss of virologic response

RESISTANCE

ECHO Study (48 weeks)

Virologic failures related to ineffectiveness are seen in 11% of subjects receiving rilpivirine compared to 4% in those receiving efavirenz. Virological failures related to the development of resistance mutations are seen in 13% of subjects receiving rilpivirine compared to 6% in those receiving efavirenz.

Mutations that have occurred during treatment with rilpivirine lead to greater resistance to other NNRTIs compared to those that have occurred with the use of efavirenz. Consequently, subsequent treatment options with rilpivirine are more limited.

THRIVE Study (48 weeks)

Virologic failures related to ineffectiveness are seen in 7% (24) of subjects receiving rilpivirine compared to 5% (18) in those receiving efavirenz. Virological failures related to the development of resistance mutations are observed in 8% of subjects receiving rilpivirine compared to 6% in those receiving efavirenz.

Combined ECHO and THRIVE analysis in patients with VL < 100 000 copies/mL

The samples obtained for the resistance analyzes consisted of 8.0% (23/288) of RPV + FTC/TDF subjects and 4.7% (12/255) of EFV + FTC/TDF subjects. Most samples were obtained during the first 48 weeks and five additional samples (2%) in the two treatment groups during weeks 48 to 96. Genotypic data were available for isolates of 22 subjects in the RPV + FTC/TDF group and 10 in the EFV + FTC/TDF group.

The proportions of isolates with mutations for NNRTI were low for both treatment groups (3.5% and 1.2%, respectively), with E138K (1.4%) and K103N (1.2%) reported for RPV + FTC/TDF and EFV + FTC/TDF, respectively. Nine subjects taking RPV + FTC/TDF (3.1%) have developed mutations for NRTIs and none with EFV + FTC/TDF. The most frequently observed NRTI mutations with RPV + FTC/TDF were M184I (2.8%) followed by M184V (0.7%). Mutation K65R, associated with resistance to TDF, was not detected in either treatment group.

ADVERSE REACTIONS

In short

  • Neuropsychiatric effects
  • Dizziness
  • Sleeping troubles
  • Rashes

As for the safety profile, rilpivirine is reported to be well tolerated and more favorable than efavirenz. Rilpivirine causes fewer grade 2 or higher side effects (such as those on the central nervous system), fewer changes in lipid profile and less risk of skin rashes.

THRIVE Study (48 weeks)

Grade 2 to 4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than with efavirenz (31% [104]; p < 0.0001). Less skin rash and dizziness (p < 0.0001) and increases in lipid levels were significantly lower with rilpivirine than with efavirenz (p < 0.0001).

Discontinuations due to adverse reactions were observed in 4% (15) of subjects receiving rilpivirine compared to 7% (25) of those receiving efavirenz.

ECHO Study (48 weeks)

Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [55 patients]) than they were with efavirenz (31% [108]; p < 0.0001). Fewer rashes, dizziness and abnormal dreams with rilpivirine (p < 0.0001) and increases in lipid levels were significantly lower with rilpivirine than with efavirenz (p < 0.0001).

Discontinuations due to adverse reactions were observed in 2% (8) of subjects receiving rilpivirine compared to 8% (27) of those receiving efavirenz.

THRIVE and ECHO Studies (analyzes combined at 48 weeks)

Rilpivirine versus efavirenz resulted in a lower incidence of adverse events leading to treatment discontinuation (3% vs. 8%, respectively), treatment-related grade 2-4 adverse events (16% vs. 31%), rash (3% vs. 14%), dizziness (8% vs. 26%), abnormal dreams/nightmares (8% vs. 13%). There were also fewer grade 2-4 lipid abnormalities with rilpivirine.

ECHO and THRIVE Studies (week 96)
Selection of treatment-related adverse events (Grade 2–4) reported in ≥ 1% of patients

RPV + FTC/TDF
(N=550)
EFV + FTC/TDF
(N=546)

Abdominal pain

2%

2%

Nausea

2%

3%

Vomiting

1%

2%

Fatigue

2%

3%

Dizziness

1%

7%

Headache

4%

4%

Drowsiness

< 1%

1%

Abnormal dreams

2%

5%

Depression

5%

3%

Insomnia

3%

3%

Sleeping troubles

1%

1%

Skin rash

3%

10%

Decreased appetite

1%

1%

THRIVE and ECHO  Studies (combined analyzes in patients with VL <100 000 copies/mL)

Overall, RPV + FTC/TDF showed a more favorable safety profile than EFV + FTC/TDF with lower rates of discontinuation due to adverse events (2.8% versus 4.3%). The proportions of subjects with treatment-related adverse reactions or treatment-related grade 2 to 4 adverse reactions were lower in the RPV + FTC/TDF group compared to the EFV + FTC/TDF group (47% vs. 62% and 17% vs. 30%, respectively; p <0.001).

ECHO and THRIVE Studies
(Combined analyzes in patients with a VL <100 000 copies/ml – Week 96)
Adverse reactions

RPV + FTC/TDF
(N=288)
EFV + FTC/TDF
(N=255)
Neurological and psychiatric effects
(mostly grade 1-2)
19% 38%

p = 0.018

Dizziness 10% 28% p < 0.001
Abnormal dreams and nightmares 7.6% 14% p = 0.025
Skin rash 2.1% 10.6% p < 0.001

ECHO and THRIVE Studies
(Combined analyzes in patients with a VL <100 000 copies/ml – Week 96)
Laboratory abnormalities

RPV + FTC/TDF
(N=288)
EFV + FTC/TDF
(N=255)
Laboratory abnormalities (Grade 3-4) 11% 21%

p = 0.002

Increase in transaminases (ALT and AST) (Grade 2–4) 6.6% 12.9% p = 0.018
Hyperbilirubinemia (Grade 2–4) 4.2% 0% p = 0.001
Total cholesterol (Grade 2–3) 7% 22% p < 0.001
Total cholesterol (Grade 1) 23% 35% p < 0.001
LDL Cholesterol (Grade 2–3) 9% 19% p = 0.001
LDL Cholesterol (Grade 1) 19.9% 32.7% p < 0.001

Median TC, LDL-C and triglycerides, all decreased with RPV + FTC/TDF, while these parameters increase with EFV + FTC/TDF (p <0.001).

High density lipoprotein cholesterol (HDL-C) increases further with EFV + FTC/TDF compared to RPV + FTC/TDF (median values of 8.9 vs. 1.9 mg/dL, p <0.001)

Fewer subjects on RPV + FTC/TDF compared to EFV + FTC/TDF required lipid-lowering drugs (2.1% vs. 6.3%, p = 0.016).

Variation in serum creatinine

Median change in serum creatinine at week 96 was small for both treatment groups (RPV + FTC/TDF 0.10 mg/dL and EFV + FTC/TDF 0.03 mg/dL), but higher for the RPV treatment group (p <0.001). Most of the changes in serum creatinine were grade 1 elevations (RPV + FTC/TDF 6.3% and EFV + FTC/TDF 1.2%) and grade 2 to 4 elevations occurred in only 1% of subjects in the two treatment groups. The median EGFR at week 96 remained within the normal range.

Bone density

At week 96, there was no difference between the treatment groups for changes in bone mineral density and fat distribution at the limb levels. Median changes in bone mineral density were -0.015 g/cm2 for RPV + FTC/TDF and -0.014 g/cm2 for EFV + FTC/TDF. The median fat change in limb levels was +501 grams for RPV + FTC/TDF and +578 grams for EFV + FTC/TDF.

Skin and hypersensitivity reactions

Overall, most of the rashes were grade 1 or 2. They occurred during the first four to six weeks of therapy and did not require stopping Odefsey®.

Severe skin and hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported (Phase 3: less than 1%). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with elevations of liver transaminases.

Odefsey® must be stopped immediately if a severe skin reaction or hypersensitivity reaction is suspected.

Mood disorder

Depressive disorders (altered mood, depression, dysphoria, negative thoughts, suicidal thoughts and attempted suicide) have been reported with Odefsey®.

In a phase 3 study (N=1,368) for 96 weeks, the incidence (regardless of causation, severity) was 9%. Most of the events were mild or moderate in intensity.

It is recommended that patients with severe depressive symptoms be assessed promptly to assess if the symptoms are related to Odefsey® and to determine whether the risks of continued treatment outweigh the benefits.

Immune reconstitution inflammatory syndrome (IRIS)

This effect can be seen with any antiretroviral therapy. An inflammatory response to poorly progressive or residual opportunistic infections (e.g. Mycobacterium avium complex, cytomegalovirus, Pneumocystis jerovinci pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.

For management of adverse reactions associated with antiretrovirals, see section management of adverse reactions.

MECHANISM OF ACTION

Rilpivirine

Non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine class

Emtricitabine et ténofovir alafénamide

Reverse transcriptase inhibitors

PHARMACOKINETICS

Bioavailability

Rilpivirine : Absolute bioavailability is not known
It is recommended that rilpivirine be taken with a meal. When taken with a meal, the absorption of rilpivirine is increased.
Indeed, a moderate fat meal increases the AUC and Cmax of rilpivirine by 57% and 89%, respectively.

Tmax

Rilpivirine : 4 h
Emtricitabine : 2 h
Tenofovir alafenamide : 1.5 h

Elimination T½ (plasma)

Rilpivirine : 45 h
Emtricitabine : 10 h
Tenofovir alafenamide : 0.51 h (tenofovir 32.37 h)

T½ intracellular

Tenofovir alafenamide : 150-180 h in mononuclear peripheral blood cells

Metabolism

Rilpivirine : CYP3A
Emtricitabine : not significantly metabolized
Tenofovir alafenamide : cathepsin A and CES1; transported by P-gp and BCRP

Elimination

Rilpivirine : 85% in faeces (25% unchanged) and urinary excretion (6.1%) (< 1% unchanged)
Emtricitabine : ~86% urinary excretion and ~14% in faeces unchanged
Tenofovir alafenamide : urinary excretion < 1% unchanged and in faeces; in urine by glomerular filtration and by active tubular secretion (tenofovir)

Binding to plasma proteins

Rilpivirine : 99.7%
Emtricitabine : < 4%
Tenofovir alafenamide : ~80%

PREGNANCY AND BREAST FEEDING

There is not enough data to assess the safety and efficacy of Odefsey® in pregnant or breastfeeding women.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

  • Hypersensitivity to the active or inactive molecules contained in the tablet.

Drugs interactions

  • Co-administration with drugs which induce CYP3A enzymes or which increase gastric pH as it may cause loss of virological response and possible resistance to Odefsey® : carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentin, systemic dexamethasone (more than one dose), St. John’s wort (Hypericum perforatum), proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole).

Precautions

Patient co-infected with hepatitis B

  • If Odefsey® is discontinued in a patient co-infected with HBV, caution should be exercised. Indeed, severe acute exacerbations of hepatitis B (hepatic decompensation and hepatic failure) have been observed in patients co-infected with HBV and HIV-1. Therefore, stopping treatment with Odefsey® without initiating alternative hepatitis B therapy is not recommended.

Administration with other antiretrovirals

  • Odefsey® should not be coadministered with other antiretrovirals that contain rilpivirine, emtricitabine, tenofovir alafenamide, tenofovir DF or lamivudine (Atripla, Biktarvy, Cabenuva, Combivir, Complera, Delstrigo, Descovy, Dovato, Edurant, Emtriva, Epivir, Heptovir, Genvoya, Juluca, Kivexa, Symtuza, Stribild, Triumeq, Trizivir, Truvada, Vemlidy, Viread), nor with adefovir dipivoxil (Hepsera).

Drugs interactions

  • Co-administration with moderate CYP3A4 inducers such as rifabutin, antacids or laxatives containing aluminum and/or calcium carbonate, magnesium, calcium or iron supplements, H2 receptor antagonists, may decrease rilpivirine concentration, resulting in loss of virological response and possible resistance to rilpivirine or the NNRTI class.

See product monograph or the section on drug interactions for more details.

Hypersensitivity reactions

  • Severe skin and hypersensitivity reactions have been reported (see adverse reactions section). You should therefore be on the lookout for this risk of reaction and permanently stop Odefsey® if such a reaction is suspected.

FURTHER INFORMATION

Administration

No data on whether the tablet can be cut or crushed. The manufacturer does not recommend it because tenofovir alafenamide (TAF) has a bitter, burnt taste and rilpivirine is insoluble in water over a wide range of pH.

Storage

Store the tablets at a maximum temperature of 30° C.

RÉFÉRENCES

  • Rilpivirine/emtricitabine/tenofovir alafenamide (Odefsey), Gilead Sciences, Ontario, Canada, Nov 13 2019.
  • Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet; 2011 Jul 16; 378(9787): 229-37.
  • Cohen CJ, Molina JP, Cassetti I, Chetchotisakd P, Lazzarin A et al. Week 96 Efficacy and Safety of Rilpivirine in Treatment-Naive, HIV-1 Patients in Two Phase III Randomized Trials. AIDS. 2013 Mar 27; 27(6): 939-50.
  • Molina JM, Cahn P, Grinsztejn B, et coll. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active controlled trial. Lancet; 2011; 378: 238-46.
  • Behrens G, Rijnders B, Nelson M et al. Rilpivirine Versus Efavirenz with Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-Naive HIV-1–Infected Patients with HIV-1 RNA < 100,000 Copies/mL: Week 96 Pooled ECHO/THRIVE Subanalysis. AIDS PATIENT CARE and STDs. 2014; 28 (4): 168-175.
  • Rimsky L, Van Eygen V, Hoogstoel A, et al. 96-week resistance analyses of rilpivirine in treatment-naive, HIV-1- infected adults from the ECHO and THRIVE Phase III trials. Antivir Ther 2013; 18: 967–977.
  • Molina JM, N Clumeck N, Orkin C et al. Week 96 Analysis of Rilpivirine or Efavirenz in HIV-1-infected Patients With Baseline Viral Load ≤ 100 000 copies/mL in the Pooled ECHO and THRIVE Phase 3, Randomized, Double-Blind Trials. HIV Med 2014 Jan; 15(1): 57-62.
  • Foisy M, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., AAHIVP, Northern Alberta Program, KEC Site,Edmonton, Alberta, Sarah Lamb, PharmD Student (2017 updates), and A. Tseng, Pharm.D, AAHIVP, Toronto General Hospital. ORAL ANTIRETROVIRAL ADMINISTRATION: INFORMATION ON CRUSHING AND LIQUID DRUG FORMULATIONS.

ABBREVIATIONS

RPV, rilpivirine; FTC, emtricitabine; TAF, tenofovir alafenamide; DIE, once daily; CrCl, creatinine clearance; NNRTI, non-nucleoside reverse transcriptase inhibitor; EFV, efavirenz; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; TDF, tenofovir disoproxyl furamate; EGFR, Epidermal Growth Factor Receptor.

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