Cette page a été mise à jour le 29 October 2020

FORMULATION(s)

Fabricant : ViiV Healthcare

DOSAGE

Adult dosage

1 tablet DIE with a meal. For missed doses, the product monograph recommends an interval of 12 hours.

Take the missed dose as soon as possible, unless there are only 12 hours or less before the next dose. Do not double the dose.
* See bioavailability in the pharmacokinetics section.

Pediatric dosage

Safety and efficacy have not been established in pediatric population.

Adjustment in renal impairment

No adjustment required in patients with renal impairment. However, the DHHS guidelines recommend monitoring of adverse reactions in patients with a CrCl <30 mL/min, since there is little or no data for this population.

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

Study in patients with virological suppression and switching from their actual antiretroviral therapy to the combination dolutegravir and rilpivirine

Study

Comparator groups

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

Types of patients

SWORD-1 and SWORD-2
Transfer study

DTG + RPV (N=513) vs CAR* (N=511) at 48 weeks.

After 48 weeks of observation. The AAT group was also transferred to DTG + RPV.

Week 48
Noninferiority of DTG + RPV (95% vs 95%, 95% CI -3,0% to 2,5%).
Lack of response (VL > 50 copies/mL) observed in less than 1% in each group.

Week 100
89% of viral suppression with DTG + RPV.
Lack of response (VL > 50 copies/mL) observed in 3% of patients.

Patients who may have received one or two antiretroviral therapies but have not had previous virologic failure.
Stable virologic suppression (< 50 copies/mL) for ≥ 6 months.
Patients not requiring treatment for hepatitis B.

*CAR : Current ART regimen containing 2 NRTIs associated either with an INI, or with a NNRTI or with a PI

RESISTANCE

After 48 weeks, a NNRTI-resistance mutation was identified (K101 K/E) in a patient with virological failure. No resistance to integrase inhibitors was observed.

After 100 weeks of observation, 13 patients failed and NNRTI-resistance mutations were observed in three of these patients. The mutations identified were K101K/I, E101E, E138A and M230M/L. K101E and W138A were identified in the same patient in the genotype done before initiating therapy.

A mutation for integrase inhibitors (G193E) was observed in one patient. However, it was present in the genotype before initiating the study.

ADVERSE REACTIONS

In short

  • Headache
  • Digestive effects like diarrhea and nausea
  • Neuropsychiatric effects like anxiety or insomnia
  • Fatigue
  • Diarrhea
  • Potential weight gain observed in retrospective cohort studies and especially in black women

SWORD-1 and SWORD-2 studies
(Pooled analyses, Week 48)
Grade 1 to 4 adverse reactions that occurred during the study (Suspected adverse drug reactions)

DTG + RPV
(N=513)
CAR*
(N=511)

Diarrhea

6% (2%)

5% (< 1%)

Nausea

(1%)

(0%)

Fatigue

(< 1%)

(0%)

Headache

8% (2%)

5% (0%)

Dizziness

(1%)

(< 1%)

Arthralgia

4%

2%

Insomnia

3% (< 1%†)

2% (0%†)

Depression

3% (< 1%†)

1% (0%†)

Anxiety

2% (< 1%†)

2% (0%†)

Abnormal dreams

1% (< 1%†)

0% (0%†)

* CAR : Current ART regimen containing 2 NRTIs associated with either an INI, a NNRTI or a PI
† Grade 2 to 4 side effects considered to be related to treatment

At week 48, among the adverse reactions of all grades, those of grade 1 were the most represented (except for headache). 2% of patients in each group had to discontinue treatment due to adverse effects related to the study drugs. A disturbance of renal and bone parameters was observed in the DTG + FTC/TDF group compared to DTG + 3TC.

At week 96, 20% vs 25% of the adverse effects observed were considered to be related to medication. As in week 48, headaches occurred in more than 1% of patients and could be of grade 2 to 5.

3% of patients in each group had to discontinue treatment due to adverse effects related to the study drugs. The effects that motivated the discontinuation of the medication are neuropsychiatric effects in each of the groups. Discontinuation due to renal and bone effects has also been seen in patients on DTG + FTC/TDF.

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

Impact on kidney and bone parameters

  • An improvement in bone parameters is observed at 48 weeks. No further improvement on these same parameters was observed at week 100 compared to week 48.
  • Improvement in renal parameters is observed at week 48 and 100 with the transfer to DTG + RPV.

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 with a rash, constitutional symptoms, multi-organ and liver damage.

The product monograph recommends that Juluca® be discontinued immediately if there are 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. It is important to note that Juluca® therapy should not be considered as antiretroviral therapy in a patient with concomitant chronic hepatitis B.

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 jirovinci pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.

Depressive disorders

Depressive disorders have been reported with the use of rilpivirine. Patients who present with depressive symptoms (depressed mood, depression, dysphoria, major depression, mood alteration, negative thoughts, suicide attempt, suicidal ideation) following initiation of therapy containing rilpivirine should be evaluated. adequately to determine if the drug may be involved. Insomnia, depression and suicidality have been reported with integrase inhibitors, more in patients with pre-existing psychiatric conditions.

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.

Bilirubin 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.

MECHANISM OF ACTION

Dolutegravir

Integrase inhibitor

Rilpivirine

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

PHARMACOKINETICS

Bioavailability

Dolutegravir : absolute bioavailability is not known
Rilpivirine : absolute bioavailability is not known
* It is recommended to take Juluca ® with a meal. When Juluca ® is taken with a meal, the absorption of dolutegravir and rilpivirine is increased.
Indeed, a meal with a moderate fat content increases dolutegravir AUC and Cmax by 87% and 75%, respectively, compared to fasting state. For rilpivirine under the same conditions, the increase in AUC and Cmax is 57% and 89%.

Tmax

Dolutegravir : 3 h
Rilpivirine : 4 h

Elimination T½ (plasma)

Dolutegravir : 15 h (with a single dose with a moderate fat meal*)
Rilpivirine : 59.2 h (with a single dose with a moderate fat meal*)
* ~625 kcal : 125 kcal of protein (20%), 300 kcal of carbohydrates (48%) and 200 kcal of fat (32%)

Metabolism

Dolutegravir : UGT1A1 (major) and CYP3A (minor, 9.7% of the total dose)
Rilpivirine : CYP3A4

Effects on transporters

Dolutegravir: inhibitor of the OCT2 transporter and inhibits tubular secretion of creatinine and excretion of drugs that depend of OCT2 (dofetilide, fampridine and metformin); also MATE1 transporter inhibitor

Blood-plasma ratio

Dolutegravir : 0.5
Rilpivirine : 0.7

Elimination

Dolutegravir : in faeces 64 % (53 % unchanged) and urinary excretion 31 % (< 1 % unchanged)
Rilpivirine : in faeces 85 % (25 % unchanged) and urinary excretion 6.5 % (< 1 % unchanged))

Binding to plasma proteins

Dolutegravir : > 98,9 %
Rilpivirine : ~99,7 %

Pregnancy

Dolutegravir : there are no pharmacokinetic data for dolutegravir during pregnancy
Rilpivirine : there is a decrease in the exposure of total rilpivirine during pregnancy in the 2nd and 3rd trimesters compared to the postpartum period. A 21%, 29% and 35% decrease in Cmax, AUC and Cmin, respectively, was noted in the 2nd trimester compared to the postpartum period. During the 3rd trimester, a decrease of 20%, 31% and 42% of the same parameters was observed compared to the postpartum period. For free (active) rilpivirine, the decrease in pharmacokinetic parameters observed between pregnancy and the postpartum period was less pronounced. It is recommended to perform an antiretroviral therapeutic drug monitoring (TDM) before pregnancy if possible or during the first trimester. Then, the TDM should be repeated between the 16th and 20th week of gestation, at the start of the 3rd trimester and about 2 weeks after childbirth.

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

Dolutegravir : Studies in animals have shown that dolutegravir is secreted in breast milk. It is therefore not excluded that dolutegravir is present in breast milk.

Rilpivirine : It is not known if rilpivirine is excreted in breast milk.

Mothers treated with Juluca® should be advised not to breastfeed, given the risk of transmission of HIV-1 to their infants and the risk of serious adverse reactions in infants.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

  • Hypersensitivity to the active or inactive molecules contained in the tablet.
  • Concomitant administration with dofetilide, fampridine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampicin, rifapentine, proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) general action (more than one dose) and St. John’s wort (Hypericum perforatum) (see interaction module for additional details ).

Precautions

  • 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 the concentration of Juluca® and compromise effectiveness. Also, dolutegravir may increase the plasma concentration of metformin.

For safer use with drugs used in conjunction with Juluca®, consult the product monograph or the section on drug interactions.

FURTHER INFORMATION

Administration

Ideally the tablet should be swallowed whole.

No data on whether the tablet can be cut or crushed, but based on clinical judgment if Juluca® requires splitting, it should be split in half and ingested immediately with a meal. If Juluca® needs to be mashed, it should be mashed and added to a small amount of liquid or semi-solid food and consumed whole and 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 and dolutegravir.

Storage

Store the tablets at a maximum temperature of 30° C. The product monograph recommends keeping the tablets in their original packaging without removing the desiccant sachet with silica gel to protect them from humidity and tightly closed.

REFERENCES

  • Dolutegravir/Rilpivirine (Juluca), ViiV Healthcare, Quebec, Canada, Feb 5 2020.
  • 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.
  • 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
  • U.S. Department of Health and Human Services (DHHS). Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Published on december 7, 2018.
    https://aidsinfo.nih.gov/guidelines/html/3/perinatal/0 Consulted on november 30, 2019.
  • Aboud et al. AIDS 2018: Amsterdam the Netherlands. Poster THPEB047.
  • McComsey et al. 9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France. Poster TUPDB0205LB.
  • Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018 Mar 3; 391(10123): 839-849.

ABBREVIATIONS

DTG, dolutegravir; RPV, rilpivirine; DIE, once daily; CrCl, creatinine clearance; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; INIs, integrase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease 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.