Juluca®
Dolutegravir 50 mg / Rilpivirine 25 mg
Fabricant : ViiV Healthcare
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.
Safety and efficacy have not been established in pediatric population.
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.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
Types of patients |
|
SWORD-1 and SWORD-2 |
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 Week 148 |
Patients who may have received one or two antiretroviral therapies but have not had previous virologic failure. |
*CAR : Current ART regimen containing 2 NRTIs associated either with an INI, or with a NNRTI or with a PI
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 148 weeks of observation, 11 patients failed and NNRTI-resistance mutations were observed in six 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.
SWORD-1 and SWORD-2 studies
|
||
| 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
In the studies (SWORD-1 and SWORD-2), serious adverse events in 5% and 14% of patients at weeks 48 and 148, respectively, were observed in patients treated with dolutegravir and rilpivirine from baseline. Serious adverse events were observed at week 148 in 9% of patients who initially continued on their current antiretroviral therapy and who switched to dolutegravir and rilpivirine at week 52. Discontinuation of treatment was reportedly necessary in 3% (including 1% for psychiatric effects) and 8% (including 3% for psychiatric effects) of patients in the first group at weeks 48 and 148, respectively. In the second group, 4% had stopped treatment (including 1% for psychiatric effects) at week 148.
For management of adverse reactions associated with antiretrovirals, see section management of adverse reactions.
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.
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.
Integrase inhibitor
Non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine class
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%.
Dolutegravir : 3 h
Rilpivirine : 4 h
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%)
Dolutegravir : UGT1A1 (major) and CYP3A (minor, 9.7% of the total dose)
Rilpivirine : CYP3A4
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
Dolutegravir : 0.5
Rilpivirine : 0.7
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))
Dolutegravir : > 98,9 %
Rilpivirine : ~99,7 %
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.
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.
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.
For safer use with drugs used in conjunction with Juluca®, consult the product monograph or the section on drug interactions.
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.
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.
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.
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