Odefsey®
Rilpivirine 25 mg / Emtricitabine 200 mg / Tenofovir alafenamide 25 mg
Fabricant : Gilead
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.
Child or adolescent ≥ 35 kg : 1 tablet DIE with a meal.
Safety and efficacy have not been established in pediatric population < 35 kg.
CrCl ≥ 30 mL/min : No adjustment required
CrCl < 30 mL/min and ≥ 15 mL/min : Administration not recommended
Child-Pugh A or B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Dosage regimens containing rilpivirine
Clinical studies with Odefsey® have shown that :
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 |
THRIVE |
RPV + FTC/TDF (N=340) vs EFV + FTC/TDF (N=338) |
Week 48 |
ECHO + THRIVE |
RPV + FTC/TDF (N=288) vs EFV + FTC/TDF (N=255) |
Week 96 |
*ITT TBLVR : Intent to Treat – Time before loss of virologic response
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.
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.
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.
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.
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.
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.
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)
|
||
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% |
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
|
|||
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
|
|||
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.
Non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine class
Reverse transcriptase inhibitors
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.
Rilpivirine : 4 h
Emtricitabine : 2 h
Tenofovir alafenamide : 1.5 h
Rilpivirine : 45 h
Emtricitabine : 10 h
Tenofovir alafenamide : 0.51 h (tenofovir 32.37 h)
Tenofovir alafenamide : 150-180 h in mononuclear peripheral blood cells
Rilpivirine : CYP3A
Emtricitabine : not significantly metabolized
Tenofovir alafenamide : cathepsin A and CES1; transported by P-gp and BCRP
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)
Rilpivirine : 99.7%
Emtricitabine : < 4%
Tenofovir alafenamide : ~80%
There is not enough data to assess the safety and efficacy of Odefsey® in pregnant or breastfeeding women.
Drugs interactions
Patient co-infected with hepatitis B
Administration with other antiretrovirals
Drugs interactions
See product monograph or the section on drug interactions for more details.
Hypersensitivity reactions
No data on whether the tablet can be cut or crushed. The manufacturer does not recommend dissolving rilpivirine because it is insoluble in water over a wide pH range. But based on clinical judgment, if Odefsey® requires fractionation, it should be halved and ingested immediately with a meal. If Odefsey® needs to be crushed, it should be crushed and added to a small amount of liquid or semi-solid foods and consumed whole immediately with a meal. In the absence of detailed data on this method of administration, the clinician may consider performing a therapeutic drug monitoring (TDM) for rilpivirine.
Store the tablets at a maximum temperature of 30° C.
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.