Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Hypersensitivity reactions
Hypersensitivity reactions have been reported with dolutegravir, and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.
dolutegravir/rilpivirine 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 dolutegravir/rilpivirine after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids and weight, there is in some cases evidence for a treatment effect. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

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) (see sections 4.5 and 5.1). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Dolutegravir/rilpivirine 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 dolutegravir/rilpivirine 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.

Interactions with other medicinal products

Dolutegravir/rilpivirine should not be administered with other antiretroviral medicinal products for the treatment of HIV (see section 4.5).

Juluca should not be taken with any other medicinal product containing dolutegravir or rilpivirine, except in case of co-administration with rifabutin (see section 4.5).

H2-receptor antagonists
Dolutegravir/rilpivirine should not be co-administered at the same time as H2-receptor antagonists. These medicinal products are recommended to be administered 12 hours before or 4 hours after dolutegravir/rilpivirine (see section 4.5).

Antacids
Dolutegravir/rilpivirine should not be co-administered at the same time as antacids. These medicinal products are recommended to be administered 6 hours before or 4 hours after dolutegravir/rilpivirine (see section 4.5).
Supplements and multivitamins
Calcium or iron supplements, or multivitamins should be co-administered at the same time as dolutegravir/rilpivirine, with a meal. If calcium or iron supplements, or multivitamins cannot be taken at the same time as dolutegravir/rilpivirine, these supplements are recommended to be administered 6 hours before or 4 hours after taking dolutegravir/rilpivirine (see section 4.5).

Metformin
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping co-administration of dolutegravir/rilpivirine with metformin, to maintain glycaemic control (see section 4.5). Metformin is eliminated renally and therefore it is of importance to monitor renal function when co-treated with dolutegravir/rilpivirine. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.

Immune Reconstitution 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 medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Juluca has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Juluca.
The clinical status of the patient and the adverse reaction profile of Juluca should be borne in mind when considering the patient's ability to drive or operate machinery.