Juluca

/ GSK

The recommended dose of Juluca is one tablet once daily. Juluca must be taken with a meal.
Separate preparations of dolutegravir or rilpivirine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the Summary of Product Characteristics for these medicinal products.
Missed doses: If the patient misses a dose of Juluca, the patient should take Juluca with a meal as soon as possible, providing the next dose is not due within 12 hours. If the next dose is due within 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.
If a patient vomits within 4 hours of taking Juluca, another Juluca tablet should be taken with a meal. If a patient vomits more than 4 hours after taking Juluca, the patient does not need to take another dose of Juluca until the next regularly scheduled dose.
Elderly: There are limited data available on the use of Juluca in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients.
Renal impairment: No dosage adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease, the combination of Juluca with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population.
Hepatic impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Juluca should be used with caution in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh score C); therefore Juluca is not recommended in these patients.
Paediatric population: The safety and efficacy of Juluca in children and adolescents aged less than 18 years have not yet been established.
Pregnancy: The safety and efficacy of Juluca in pregnancy have not yet been established. Limited data are available regarding the use of dolutegravir during pregnancy. Lower exposures of dolutegravir and rilpivirine were observed during pregnancy. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended.
Method of administration: Oral use Juluca must be taken orally, once daily with a meal. It is recommended that the filmcoated tablet be swallowed whole with water and not be chewed or crushed.

Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor.

Hypersensitivity to the active substances or to any of the excipients.
Co-administration with the following medicinal products:
– dofetilide;
– carbamazepine, oxcarbazepine, phenobarbital, phenytoin;
– rifampicin, rifapentine;
– proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole;
– systemic dexamethasone, except as a single dose treatment;
– St John’s wort (Hypericum perforatum).

Transmission of HIV: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Hypersensitivity reactions: Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Juluca should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with Juluca after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Cardiovascular: At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Juluca should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.
Opportunistic infections: Patients should be advised that Juluca does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients with hepatitis B or C: No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus.
Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Monitoring of liver function is recommended in patients with hepatitis B and/or C co-infection.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Excipients: Juluca contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The most frequently reported adverse reactions considered possibly or probably related to the combined administration of dolutegravir plus rilpivirine in 513 HIV-1 infected subjects in the Phase III clinical trials (see section 5.1), were diarrhoea (2%) and headache (2%).
The most severe adverse reaction, possibly related to the treatment with dolutegravir (from pooled from Phase IIb and Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects.
See prescribing information for full details.

Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Juluca
contains dolutegravir and rilpivirine, therefore any interactions identified with these active substances are relevant to Juluca. Interaction studies have only been performed in adults.
Effect of other medicinal products on the pharmacokinetics of dolutegravir and rilpivirine: Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT)1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, cytochrome P450 (CYP)3A4, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP); therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of Juluca and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration.
The absorption of dolutegravir is reduced by certain anti-acid medicinal products.
Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of Juluca with medicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine, which could reduce the therapeutic effect of Juluca. Co-administration of Juluca with medicinal products that inhibit
CYP3A may result in increased plasma concentrations of rilpivirine.
Co-administration of Juluca with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of Juluca.
Effect of dolutegravir and rilpivirine on the pharmacokinetics of other medicinal products: Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp.
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1). In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase
plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, metformin).
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT)1 and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.
Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
Rilpivirine inhibits P-gp in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicinal products transported by P-gp that are more sensitive to intestinal P-gp inhibition, e.g. dabigatran etexilate.
Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown.
See prescribing information for full details.

Pregnancy: There are limited data from the use of rilpivirine in pregnant women. The use of Juluca during pregnancy is not recommended.
Lactation: It is unknown whether dolutegravir or rilpivirine are excreted in human milk. It is recommended that HIV infected women do not breast-feed
their infants under any circumstances in order to avoid transmission of HIV.
See prescribing information for full details.

No specific symptoms or signs have been identified following acute overdose with dolutegravir or rilpivirine apart from those listed as adverse reactions.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of Juluca. If overdose occurs, the patient should be treated supportively with appropriate monitoring, including monitoring of vital signs and ECG (QT interval), as necessary. As dolutegravir and rilpivirine are highly bound to plasma proteins, dialysis is unlikely to result in significant removal of the active substances.