Pifeltro®
Doravirine 100 mg
Fabricant : Merck
1 tablet DIE with or without food. For the forgotten doses, the product monograph has no specific data.
It recommends taking the missed dose as soon as possible, unless there is little time before the next dose. Do not double the dose.
Safety and efficacy have not been established in pediatric population (< 18 years of age).
No dose adjustment with mild, moderate or severe renal impairment. However, doravirine has not been studied in patients with end-stage renal disease or when the patient is on dialysis.
Child-Pugh A ou B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Doravirine has been studied in treatment-naive patients as well as in patients undergoing treatment with virologic suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
|
DRIVE-FORWARD |
DOR + 2 NRTIs (N=383) vs DRV/r + 2 NRTIs (N=383) |
Week 48 |
|
DRIVE-AHEAD |
DOR/3TC/TDF (N=364) vs EFV/FTC/TDF (N=364) |
Week 48 |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL at 48 weeks) |
Types of patients |
|
DRIVE-SHIFT |
DOR/3TC/TDF (N=447) vs CAR* (N=223) |
Week 24 |
Patients who may have received antiretroviral therapy but have not had previous virologic failure. |
* CAR : Current initial antiretroviral therapy with 2 NRTIs in combination with a PI boosted by ritonavir or cobicistat, elvitegravir boosted by cobicistat, or a NNRTI
The development of resistance to doravirine was observed in 7/30 subjects in the resistance analysis subgroup (CV more than 400 copies/mL at the time of failure or cessation of therapy). Emerging reverse transcriptase substitutions that confer resistance to doravirine included at least one of the following : A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R et Y318Y/F.
Among the 7 subjects who acquired resistance to doravirine, 6 had phenotypic resistance to efavirenz and nevirapine, 3 had phenotypic resistance to rilpivirine and 2 had partial resistance to etravirine.
Compared to other agents in the studies (DRIVE-FORWARD and DRIVE-AHEAD) :
DRIVE-FORWARD DRV/r: No resistance to darunavir was observed in the 11 subjects in the resistance analysis subgroup.
DRIVE-AHEAD EFV/FTC/TDF : resistance to efavirenz was observed in 12/24 of the resistance analysis subgroup.
What has been observed for doravirine in all studies :
• Doravirine displays sensitivity in the presence of the K103N, Y181C, G190A, E138K mutations or the double K103N/Y181C mutation, the main mutations associated with NNRTIs.
• Doravirine exhibited a 3-fold smaller variation of IC50 against strains K103N, Y181C and K103N/Y181C.
• Doravirin exhibited a 9-fold smaller variation in IC50 against most single mutant viruses, including A98G,E138A/G/K/Q, G190A, K101E/P, K103N/S, L100I, P236L, V106M, V108I, V197D, V90I, Y181C/V and Y188H/C.
• Substitutions including G190E/S, V106A, Y188L and M230L reduce the sensitivity of doravirine by more than 10 times.
• Substitutions G190S, Y188L and M230L confer 95-fold greater resistance.
According to clinical studies, doravirine was well tolerated in the majority of patients. Indeed, no moderate or severe side effects with a frequency greater than or equal to 2% were observed.
The most frequently reported adverse reaction was nausea in 6% of patients of all grade.
The product monograph reports serious side effects with a frequency of less than 1% for nausea, vomiting, asthenia, insomnia and nightmares.
DRIVE-FORWARD Study
|
||
| DOR + 2 NRTIs (N=383) |
DRV/r + 2 NRTIs (N=383) |
|
|
Nausea |
7% |
8% |
|
Vomiting |
2% |
1% |
|
Diarrhea |
5% |
3% |
|
Fatigue |
5% |
2% |
|
Dizziness |
3% |
2% |
|
Headache |
6% |
3% |
|
Insomnia |
1% |
2% |
|
Sleep disorder |
2% |
< 1% |
|
Drowsiness |
0% |
< 1% |
|
Strange dreams |
1% |
< 1% |
|
Nightmares |
< 1% |
< 1% |
|
Skin rash |
< 1% |
< 1% |
In these clinical studies, all of the side effects observed at week 48 were similar to week 96.
The most common adverse reactions were diarrhea in 5% in the doravirine group and 13% in the darunavir/r group, nausea (7% vs 8%) and headache (6% vs 3%).
Discontinuation of treatment due to adverse reactions was observed in 1.6% of subjects in the doravirine group compared to 3.1% of subjects in the DRV/r group.
DRIVE-AHEAD Study
|
||
| DOR/3TC/TDF (N=364) |
EFV/FTC/TDF (N=364) |
|
|
Nausea |
5% |
7% |
|
Vomiting |
2% |
3% |
|
Diarrhea |
3% |
5% |
|
Fatigue |
4% |
3% |
|
Dizziness |
7% |
32% |
|
Headache |
4% |
4% |
|
Insomnia |
4% |
5% |
|
Sleep disorder |
< 1% |
2% |
|
Drowsiness |
3% |
7% |
|
Strange dreams |
5% |
9% |
|
Nightmares |
2% |
4% |
|
Skin rash |
2% |
9% |
The most frequent adverse reactions were dizziness in 8.8% in the doravirine group and 37.1% in the efavirenz group, sleep disturbances (12.1% vs 25.2%) and impaired sensorium (4.4% vs 8.2%).
Discontinuation of treatment related to adverse reactions was observed in 3% of subjects in the doravirine group compared to 6.6% of subjects in the EFV/FTC/TDF group.
For management of side effects associated with antiretrovirals, see section information on adverse drug reactions.
Lipid profile
Doravirine has the advantage of having a neutral effect on lipids. Compared to DRV/r and EFV, the differences were statistically significant and showed superiority to doravirine. In addition, the DRIVE-SHIFT study shows an improvement in the lipid profile of subjects who switch from a combination of PIs/ritonavir-based antiretroviral therapy to doravirine.
Hypersensitivity reactions
Severe hypersensitivity and skin reactions are possible with the NNRTI class. According to the product monograph, moderate or severe rashes were observed in 0.3% of patients who participated in the DRIVE-FORWARD and DRIVE-AHEAD studies.
If the patient has a skin rash with systemic symptoms, stop taking doravirine immediately.
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.
Non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from pyridinone; it blocks the replication of HIV by the non-competitive inhibition of reverse transcriptase.
64 %
15 h
2 h
CYP3A4
60.5 L
Unchanged urinary excretion is minor (6%) and bile secretion is not expected to be significant.
76 %
Based on existing data, and due to the lack of studies on the effects of this medication in pregnant or breastfeeding women, it is impossible to comment on the safety of doravirine during pregnancy and breastfeeding.
Professionals are also encouraged to report pregnancy cases with a view to adding them to the register :
www.apregistry.com/ Telephone : 1-800-258-4263 Fax : 1-800-800-1052.
For safer use with drugs used concomitantly Pifeltro®, consult the product monograph or the section on drugs interactions.
No data on whether the tablet can be cut or crushed. The company recommends that you do not cut or crush it and swallow it whole.
Store the tablets at room temperature (15° C to 30° C).
DOR, doravirine; DIE, once daily; CAR, current initial ART regimen; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; DRV/r, darunavir/ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; EFV, efavirenz; FTC, emtricitabine; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; VL, viral load.
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