Tivicay®
Dolutegravir 50 mg
Dolutegravir 25 mg
Dolutegravir 10 mg
Dolutegravir 5 mg
Fabricant : ViiV Healthcare
Tivicay® must be administered in combination with other antiretrovirals.
Patients who have never received integrase inhibitors : 1 tablet of 50 mg DIE with or without food.
Patients with documented or suspected resistance to integrase inhibitors : 1 tablet of 50 mg BID with or without food.
The recommended daily dose of dispersible tablets for adults is 30 mg (6 tablets of 5 mg).
Tivicay® tablets are not milligram-for-milligram interchangeable with dispersible tablets because their pharmacokinetic profiles are different.
For missed doses, the product monograph recommends taking the missed dose as soon as possible, unless there are 4 hours or less left before the next dose. Do not double the dose.
| Weight (kg) | Dosage dispersible tablets | Dosage tablets |
| 3 to < 6 | 5 mg DIE – (1 x 5 mg) | – |
| 6 to < 10 | < 6 months : 10 mg DIE – (2 x 5 mg) ≥ 6 months : 15 mg DIE – (3 x 5 mg) |
– |
| 10 to < 14 | 20 mg DIE – (4 x 5 mg) | – |
| 14 to < 20 | 25 mg DIE – (5 x 5 mg) | 40 mg DIE – (4 x 10 mg) |
| ≥ 20 | 30 mg DIE – (6 x 5 mg) | 50 mg DIE – (1 x 50 mg) |
According to the product monograph, not recommended < 4 weeks or < 3 kg, or infected with HIV 1 virus and with suspected or confirmed resistance to ISTIs because efficacy and safety have not been established in this population.
No adjustment necessary in patients who have never received INIs with renal impairment.
Clcr < 30 mL/min : Caution is advised in patients with resistance to INIs (requiring a 50 mg BID dose), as we observed a decrease in the concentration of dolutegravir which could compromise efficacy and lead to the development of drug resistance.
There are limited data on the use of dolutegravir in patients on dialysis.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Tivicay® has been studied in treatment-naïve patients as well as in patients changing treatment with virologic suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
|
SPRING-2 |
DTG 50 mg DIE + 2 INTI (N=411) vs |
Week 96 (Snapshot algorithm) |
|
SINGLE |
DTG + ABC/3TC (N=414) vs EFV/FTC/TDF (N=419) |
Week 96 (Snapshot algorithm) |
|
ARIA (study conducted in women) |
DTG/ABC/3TC (N=250) vs atazanavir/r + TDF/FTC (N=249) |
Week 48 (Snapshot algorithm) |
|
FLAMINGO |
DTG + ABC/3TC or TDF/FTC (N=242) vs DRV/r + ABC/3TC or TDF/FTC (N=242) |
Week 96 (Snapshot algorithm) |
|
GS-US-380-1489 |
DTG/ABC/3TC (N=315) vs BIC/FTC/TAF (N=314) |
Week 96 (Snapshot algorithm) |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
Types of patients |
|
SAILING |
DTG + OBT* (N=354) vs RAL + OBT* (N=351) |
Week 48 (Snapshot algorithm) : |
Showing resistance to at least two classes of antiretroviral drugs and having never received an integrase inhibitor. |
|
STRIIVING † |
DTG/ABC/3TC (N=275) vs continue current regimen (2 NRTIs with a PI, NNRTI or INI) (N=278) |
Week 24 : |
Virological suppression since ≥ 6 months; without hepatitis B infection and not requiring treatment for hepatitis C, not carrying the HLA-B*5701 allele. |
* OBT : Optimized background treatment
† Patients with a history of single or dual NRTI therapy were excluded from the study.
In studies in patients who have never received antiretrovirals or when changing therapy in the presence of virologic suppression, Tivicay® has been shown to be very effective provided that dolutegravir and at least one of the two NRTIs which accompany them are active. In contrast, functional monotherapy of dolutegravir was associated with a significant risk of resistance.
The most common integrase inhibitor resistance mutations in people with VF on a dolutegravir-containing regimen were R263K, G118R, N155H, and Q148H/R, with the R263K and G118R mutations predominant in those previously naive to integrase inhibitors. The R263K mutation reduced sensitivity to dolutegravir by approximately 2-fold, while the G118R mutation generally reduced sensitivity to dolutegravir > 5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations.
SPRING-2 Study
|
||
| DTG 50 mg DIE + 2 NRTIs * (N=411) |
RAL 400 mg BID + 2 NRTIs * (N=411) |
|
|
Diarrhea |
14% |
13% |
|
Nausea |
15% |
14% |
|
Headache |
14% |
13% |
|
Nasopharyngitis |
13% |
14% |
|
Dizziness |
6% |
6% |
|
Insomnia |
6% |
5% |
|
Depression |
6% |
6% |
|
Anxiety |
4% |
5% |
* ABC/3TC or TDF/FTC
In the SPRING-2 study (96 weeks), adverse reactions led to discontinuation of therapy in 2% of patients in both groups. No patient in the dolutegravir group and 3 patients in the raltegravir group had to stop therapy due to side effects between weeks 48 and 96. In both groups, the side effects were mainly Grades 1 and 2 (74% dolutegravir vs 73% raltegravir).
SINGLE ING114467 Study
|
||
| DTG + ABC/3TC (N=414) |
EFV/FTC/TDF (N=419) |
|
|
Insomnia |
3% |
3% |
|
Depression |
1% |
2% |
|
Abnormal dreams |
3% |
8% |
|
Dizziness |
< 1% |
5% |
|
Headache |
2% |
2% |
|
Fatigue |
2% |
2% |
|
Nausea |
< 1% |
3% |
|
Diarrhea |
< 1% |
2% |
|
Skin rash |
< 1% |
3% |
|
Vertigo |
0% |
2% |
In the SINGLE study, 2-3% of participants on DTG + ABC/3TC dropped out due to adverse effects or mortality (week 96) compared to 12% of participants in the EFV/FTC/TDF group.
SAILING Study
|
||
| DTG 50 mg DIE + OBT * (N=354) |
RAL 400 mg BID + OBT * (N=361) |
|
|
Diarrhea |
20% |
18% |
|
Nausea |
8% |
8% |
|
Vomiting |
6% |
6% |
|
Abdominal pain |
5% |
1% |
|
Headache |
9% |
9% |
|
Fatigue |
4% |
7% |
|
Cough |
9% |
7% |
|
Upper respiratory tract infection |
11% |
8% |
|
Influenza |
7% |
7% |
|
Nasopharyngintis |
6% |
6% |
|
Urinary infection |
7% |
5% |
|
Arthralgia |
3% |
5% |
|
Skin rash |
5% |
5% |
* OBT : Optimized background treatment
In the SAILING study adverse reactions of any grade (Grades 1-4) occurred in 8% of patients in the dolutegravir group versus 9% of patients in the raltegravir group. Adverse reactions of Grades 4 were less than 1% in the 2 groups. Adverse reactions led to discontinuation of therapy in 3% of patients in the dolutegravir group compared to 4% in the raltegravir group.
Hypersensitivity reactions
Hypersensitivity reactions have been associated with integrase inhibitors. This reaction presents itself by a rash, constitutional symptoms, multi-organ and liver damage.
The product monograph recommends discontinuing Tivicay® immediately in the presence of signs or symptoms that may suggest a hypersensitivity reaction (severe rash or accompanied by fever, general malaise, fatigue, muscle or joint pain, vesicles, mouth sores, conjunctivitis, facial edema, hepatitis, eosinophilia or angioedema) and closely monitor the patient’s clinical condition.
Hepatotoxicity
Acute hepatitis has been reported in patients who had no pre-existing liver disease, or other identifiable risk factors. With Triumeq®, an antiretroviral containing dolutegravir, a liver transplant was required in one patient. Therefore, it is recommended to monitor the appearance of hepatotoxicity during treatment.
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 effects associated with antiretrovirals, see section adverse effects management.
Dolutegravir increases the serum concentration of creatinine via an inhibition of tubular secretion. This should not be interpreted as an impairment of kidney function. The increase usually occurs within the first four weeks of treatment and is, on average, around 10 μmol/L. This should be taken into account when estimating a patient’s kidney function. Some will subtract the serum creatinine observed when adding dolutegravir before calculating the estimated glomerular filtration rate.
A slight increase in total bilirubin (without clinical jaundice) has been observed due to competition between dolutegravir and unconjugated bilirubin for UGT1A1. This variation would not be clinically significant.
Creatine phosphokinase abnormalities (CPK) : : grade 2 (4%) and grade 3-4 (5%).
In addition, cases of myalgia or myositis coinciding with increases in CPK were reported during the program. Their link to the use of dolutegravir could not be excluded.
Increase in ALT/AST : grade 2 ALT (2%) and AST (3%), grade 3-4 ALT (> 1%) and AST (< 1%)
Integrase inhibitor
Absolute bioavailability is not known
Absorbed in the small intestine and predominantly in the duodenum according to the manufacturer
2-3 h
14 h
UGT1A1 (major) and CYP3A (minor, soit 9.7%)
17.4 L
Urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)
99%
Dolutegravir has been associated with neural tube defects in a Boswana follow-up cohort (Tsepamo study), and current data recommend avoiding dolutegravir during conception and early pregnancy. Indeed, the risk of neural tube defect is slightly increased compared to other antiretrovirals, but according to the latest analyzes it is less important than the risk presented initially. The abnormalities are said to have occurred at a rate of 0.3% when pregnant women were taking dolutegravir during periconception, while the overall prevalence during the periconception period was 0.1% for all antiretroviral therapy and 0.08% for all deliveries. Another retrospective study in Brazil (second largest surveillance cohort) and pregnancy registers did not observe neural tube defects.
In this same study when looking at women who started dolutegravir during pregnancy, only one case of neural tube defect was reported, 0.03% (N = 3840), compared to 0.05% (N = 59 520). No causal link has been established with the use of dolutegravir.
The risk in the general population would be 0.5-1 cases per 1000 live births.
Since the risk is low and dolutegravir is an antiretroviral that has the advantage of being given once a day, with few side effects and an ability to rapidly decrease viral load, the DHHS guidelines recommend dolutegravir as a preferred agent for pregnant women at all trimesters and as an alternative (after discussion of low risk) for women who are planning to become pregnant.
The DHHS guidelines have posted an appendix to guide healthcare professionals in their consultation with patients regarding dolutegravir..
Since neural tube defects occur during the first four weeks of fetal development, patients of childbearing potential should therefore be informed of the potential low risk before pregnancy. If necessary, contraception or the use of an alternative antiretroviral solution can be discussed.
Professionals are encouraged to discuss the risk of neural tube defect and to make the decision with the person concerned based on the risk observed in the literature to date. 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.
See also the pharmacokinetics section.
According to animal studies, dolutegravir may be present in human breast milk.
Because of the risk of HIV-1 transmission and the potential for adverse reactions to infants, HIV-positive mothers should be told not to breastfeed.
Drugs interactions
For a safer use of these drugs used in combination with dolutegravir, consult the product monograph or the drug interactions section.
Ideally the tablets should be swallowed whole. According to the manufacturer, all tablets can also be split in half, followed by immediate ingestion of both halves or crushed and added to a small amount of semi-solid food or liquids, all of which should be consumed immediately.
The dispersible tablets can be swallowed whole with water or dispersed in water. The amount of water to be used for the dispersion depends on the number of tablets to be administered. The tablet(s) should be completely dispersed before swallowing and the dose should be taken orally within 30 minutes. Do not chew, cut or crush the tablets.
Conserver les comprimés à une température maximale de 30° C.
DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine; DIE, once daily; Crcl, creatinine clearance; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafénamide; r, ritonavir; DRV, darunavir; BIC, bictegravir; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; INI, integrase inhibitors; VL, viral load.
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