Cette page a été mise à jour le 16 December 2021

FORMULATION(s)

Fabricant : ViiV Healthcare

DOSAGE

Tivicay® must be administered in combination with other antiretrovirals.

Adulte or adolescent dosage ≥ 12 years and ≥ 40 kg

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.

Pediatric dosage (≥ 4 weeks and ≥ 3kg)

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.

Adjustment in renal impairment

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.

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

Tivicay® has been studied in treatment-naïve patients as well as in patients changing treatment with virologic suppression.

Studies in Treatment-Naïve Patients

Study

Comparator groups

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

SPRING-2

DTG 50 mg DIE + 2 INTI (N=411) vs
RAL 400 mg BID + 2 INTI (N=411)

Week 96 (Snapshot algorithm)
Noninferiority of DTG (81% vs 76%, (CI95% 1.1% to 10%).
Lack of response (VL > 50 copies/mL) observed in 5% vs 10%.

SINGLE

DTG + ABC/3TC (N=414) vs EFV/FTC/TDF (N=419)

Week 96 (Snapshot algorithm)
Noninferiority of DTG + ABC/3TC (80% vs 72%, (CI95% 2.3% to 13.8%).
Lack of response (VL > 50 copies/ml) observed in 7% vs 8%.

ARIA (study conducted in women)

DTG/ABC/3TC (N=250) vs atazanavir/r + TDF/FTC (N=249)

Week 48 (Snapshot algorithm)
Noninferiority of DTG/ABC/3TC (82% vs 71%, CI95% 3.1% to 17.8%).

FLAMINGO

DTG + ABC/3TC or TDF/FTC (N=242) vs DRV/r + ABC/3TC or TDF/FTC (N=242)

Week 96 (Snapshot algorithm)
Noninferiority of the DTG group (80% vs 68%, CI95% 4.7% to 20.2%).

GS-US-380-1489

DTG/ABC/3TC (N=315) vs BIC/FTC/TAF (N=314)

Week 96 (Snapshot algorithm)
Noninferiority of BIC/FTC/TAF (88% vs 90%, CI95% -6.9% to 3.1%).

Study in patients who have already been treated with virologic suppression

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) :
Noninferiority of DTG (71% vs 64%, CI95% 0.7% to 14.2%).
Lack of response (VL > 50 copies/ml) observed in 20% vs 28%.

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 :
Noninferiority of DTG/ABC/3TC (85% vs 88%, CI95% -9.1% to 2.4%)

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.

RESISTANCE

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.

ADVERSE REACTIONS

In short

  • Insomnia
  • Headache
  • Fatigue
  • Digestive effects like diarrhea and nausea

Studies in patients who have never received antiretrovirals

SPRING-2 Study
(Week 96)
Adverse reactions of grades 2 to 4 reported in ≥ 2 % of participants

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
(Week 96)
Adverse reactions reported of grades 2 to 4 in ≥ 2 % of participants

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.

Study in patients experienced with antiretrovirals but who have never received integrase inhibitors

SAILING Study
(Week 48)
Adverse reactions of grades 2 to 4 in ≥ 2 % of participants

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.

Rarer but reported adverse effects with dolutegravir in studies or post-marketing

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.

IMPACT ON LABORATORY

Creatinine increase

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.

Bilirubine increase

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.

Impacts on liver enzymes and CPK observed in the SINGLE study at week 96

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%)

MECHANISM OF ACTION

Dolutegravir

Integrase inhibitor

PHARMACOKINETICS

Bioavailability

Absolute bioavailability is not known

Absorption

Absorbed in the small intestine and predominantly in the duodenum according to the manufacturer

Tmax

2-3 h

Elimination T½ (plasma)

14 h

Metabolism

UGT1A1 (major) and CYP3A (minor, soit 9.7%)

Distribution volume

17.4 L

Elimination

Urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)

Binding to plasma proteins

99%

PREGNANCY AND BREAST FEEDING

Pregnancy

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.

Breastfeeding

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.

PRECAUTIONS AND CONTRAINDICATIONS

Contrandications

  • Hypersensitivity to the active or inactive molecules contained in the tablet.
  • Concomitant administration with drugs transported by OCT2 and with a narrow therapeutic index such as dofetilide and fampridine (dalfampridine).

Precautions

Drugs interactions

  • Co-administration with potent CYP3A4 inducers such as rifampin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St. John’s Wort may decrease the concentration of dolutegravir and compromise efficacy. The dosage of dolutegravir should be adjusted to 50 mg twice a day.
  • The use of cations like calcium or iron can decrease the absorption of dolutegravir.
  • Also, dolutegravir may increase the plasma concentration of metformin.

For a safer use of these drugs used in combination with dolutegravir, consult the product monograph or the drug interactions section.

FURTHER INFORMATION

Administration for patients with swallowing difficulties

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.

Storage

Conserver les comprimés à une température maximale de 30° C.

REFERENCES

  • Dolutegravir/Abacavir/Lamivudine (Tivicay), ViiVHealthcare, Quebec, Canada, January 25, 2021.
  • Mofenson LM, Vannappagari V, Scheuerle AE, et al. Periconceptional antiretroviral exposure and central nervous system (CNS) and neural tube birth defects–data from Antiretroviral Pregnancy Registry (APR). 10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City. Abstract TUAB0101.
  • Roskam-Kwint M, Bollen P, Colbers A, Duisenberg-van Essenberg M, Harbers V et al. Crushing dolutegravir-combination tablets increases dolutegravir exposure. CROI 2017, Seattle, WA USA, February 13-16 2017. Abstract P-429.
  • Foisy M, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., Northern Alberta Program, KEC Site, Edmonton, Alberta, and A Tseng, Pharm.D, AAHIVP, Toronto General Hospital. ORAL ANTIRETROVIRAL ADMINISTRATION: INFORMATION ON CRUSHING AND LIQUID DRUG FORMULATIONS. May 2020.
  • Walmsley S, Baumgarten A, Berenguer J et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96-144 result from SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015; 70: 515-519.
  • RosKam-Kwint Marieke, Bollen P, Colbers A et al. Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure. J Antimicrob Chemother 2018; 73: 2430-2434.
  • Trottier B, Lake JE and Logue K. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label Phase IIIb study. Antiviral Therapy 2017; 22: 295–305.
  • Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falcó V et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. The Lancet HIV, 4(12), e536-e546.
  • Mariappan TT, Singh S. Gastrointestinal permeability studies using combinations of rifampicin and nucleoside analogue reverse transcriptase inhibitors in rats. Indian Journal of Pharmacology. 2007; 39(6): 284-290.
  • Molina JM, Clotet B, van Lunzen J and FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr; 2(4): e127-36.
  • Rhee, SY, Grand Pm, Tzou PL et al. A systematic review of the genetic mechanisms of dolutegravir resistance.
    J Antimicrob Chemother. 2019 Nov 1; 74(11): 3135-3149.

ABBREVIATIONS

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.

Do you have comments? They are important to us.

You can send us your suggestions after identification and we will try to answer them as soon as possible.