Dalimune 50 mg FC tablets

DALIMUNE is indicated in combination with other anti-retroviral medicines for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 18 years of age.

Posology

DALIMUNE therapy should be initiated by a medical practitioner experienced in the management of HIV infection. DALIMUNE can be taken with or without food.

Adults

Treatment-nau00efve

For patients initiating antiretroviral therapy for the first time (treatment-nau00efve) the recommended dose of DALIMUNE is 50 mg once daily. DALIMUNE should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz; nevirapine tipranavir/ritonavir; or rifampicin) (see section 4.5).

Treatment-experienced, and integrase inhibitor nau00efve

For patients who are treatment experienced and have not previously been treated with an integrase inhibitor, the recommended dose of DALIMUNE is 50 mg once daily.

Integrase inhibitor resistant

For patients with integrase inhibitor resistance, the recommended dose of DALIMUNE is 50 mg (one tablet) twice daily. Co-administration of DALIMUNE with some medicines should be avoided in this population (e.g. efavirenz; nevirapine tipranavir/ritonavir; or rifampicin) (see section 4.4 and section 4.5).

Special populations

Elderly

There are limited data available on the use of dolutegravir as in DALIMUNE in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see section 5.1 u2013 Special patient populations).

Renal impairment

No dosage adjustment is required in patients with mild, moderate or severe (CrCl < 30 ml/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis, although differences in pharmacokinetics are not expected in this population (see section 5.1 u2013 Special patient populations).

Treatment with DALIMUNE may result in an early small increase in mean serum levels by 10-14 % which may remain stable over time and is not clinically significant.

Method of administration

DALIMUNE is for oral administration and should be swallowed whole.

DALIMUNE is contraindicated in combination with dofetilide and pilsicainide. DALIMUNE is contraindicated in patients with known hypersensitivity to dolutegravir or to any of the excipients. DALIMUNE is contraindicated in moderate and severe hepatic impairment. Metformin is contraindicated in patients taking DALIMUNE.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with integrase inhibitors, including DALIMUNE and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue DALIMUNE and other suspect medicines immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with DALIMUNE or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness, or difficulty in movement.

Opportunistic infections

Patients receiving DALIMUNE should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others

Patients should be advised that current antiretroviral therapy, including DALIMUNE, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Hepatic impairment

The unbound fraction of dolutegravir in the blood is doubled in patients with moderate hepatic impairment. DALIMUNE is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).

Co-infection with Hepatitis B or C

Overall, the safety profile in patients co-infected with Hepatitis B and/or C is similar to that observed in patients without Hepatitis B and/or C co-infection, although the rates of AST and ALT abnormalities are higher in subgroup with Hepatitis B and/or C co-infection. Liver chemistry elevations consistent with immune reconstitution syndrome are observed in some patients with Hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy is withdrawn.

Changes in Laboratory chemistries

Increases in serum creatinine may occur within the first week of treatment with DALIMUNE and remain stable through 48 weeks. In treatment nau00efve patients, a mean change from baseline of 9,96 u03bcmol/l (range: -53 u03bcmol/l to 54,8 u03bcmol/l) may be observed after 48 weeks of treatment. Creatinine increases may be comparable by background NRTIs and may be similar in treatment experienced patients. As these changes do not reflect a change in the glomerular filtration rate (see section 5.1 u2013 Effects on Renal Function), it is not considered to be clinically relevant. Small increases in bilirubin (without clinical jaundice) may be observed with DALIMUNE and raltegravir (but not efavirenz). These changes are not considered clinically relevant as they may reflect competition between DALIMUNE and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see section 5.1 u2013 Metabolism). Asymptomatic creatinine phosphokinase (CPK) elevations mainly in association with exercise may occur with DALIMUNE. DALIMUNE contains mannitol and may have a laxative effect.

Metformin concentrations may be increased by DALIMUNE. Metformin is contraindicated in patients taking DALIMUNE (see section 4.3).

Co-administration of dolutegravir may potentially increase dofetilide or pilsicainide plasma concentration via inhibition of OCT2 transporter. Co-administration has not been studied. Dofetilide or pilsicainide co-administration with DALIMUNE is contraindicated due to the potential life-threatening toxicity caused by high dofetilide or pilsicainide concentration (see section 4.3).

Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of DALIMUNE medicines that may have their exposure changed by DALIMUNE (see section 4.3 and 4.5 below). The co-administration of DALIMUNE with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir and ritonavir (ATV + RTV), lopinavir and ritonavir (LPV + RTV) or darunavir and ritonavir (DRV + RTV). The recommended dose of DALIMUNE is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). DALIMUNE should not be co-administered with polyvalent cation-containing antacids. DALIMUNE is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5).

Effect of DALIMUNE on the pharmacokinetics of other medicines

In vitro, DALIMUNE demonstrated no direct, or weak inhibition (IC50 > 50 u03bcM) of the enzymes cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT1 or MRP2. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on these data, DALIMUNE is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters (e.g., reverse transcriptase and protease inhibitors, opioid analgesics, antidepressants, statins, azole antifungals (such as fluconazole, itraconazole, clotrimazole), proton pump inhibitors (such as esomeprazole, lansoprazole, omeprazole), anti-erectile dysfunction medicines (such as sildenafil, tadalafil, vardenafil), aciclovir, valaciclovir, sitagliptin, adefovir). In medicine interaction studies, DALIMUNE did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, telaprevir and oral contraceptives containing norgestimate and ethinyl estradiol.

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2). Based on this observation, DALIMUNE may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 (dofetilide, pilcicainide, metformin). Therefore, these OCT2 inhibitors are contraindicated for use with DALIMUNE (see section 4.3 and Table 1: Medicine interactions u2013 Other medicines).

Effect of other medicines on the pharmacokinetics of DALIMUNE:

DALIMUNE is eliminated mainly through metabolism by UGT1A1. DALIMUNE is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore, medicines that induce those enzymes may theoretically decrease dolutegravir plasma concentration and reduce the therapeutic effect of DALIMUNE. Co-administration of DALIMUNE and other medicines that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration. Efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir each reduced the plasma concentrations of dolutegravir significantly and require DALIMUNE dose adjustment to 50 mg twice daily. Etravirine also reduced plasma concentrations, but the effect of etravirine was mitigated by co-administration of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir. Therefore, no DALIMUNE dose adjustment is necessary when co-administered with etravirine and either lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. Another inducer, fosamprenavir in combination with ritonavir decreased plasma concentrations of dolutegravir but does not require a dosage adjustment of DALIMUNE. Caution is warranted and clinical monitoring is recommended when these combinations are given in INI-resistant patients (see Table1: Medicine Interactions u2013 HIV-1 Antiviral Medicines). A medicine interaction study with the UGT1A1 inhibitor, atazanavir, did not result in a clinically meaningful increase in the plasma concentrations of dolutegravir. Tenofovir, ritonavir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, bocepravir, telaprevir, prednisone, rifabutin, and omeprazole had no or a minimal effect on dolutegravir pharmacokinetics, therefore no DALIMUNE dose adjustment is required when co-administered with these medicines.

Women of childbearing potential

Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of DALIMUNE in women of childbearing potential to exclude inadvertent (unintentional) use of DALIMUNE during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.

Pregnancy

Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0,19 %) compared to non-dolutegravir regimens (0,11 %). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account.

Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known.

Breastfeeding

HIV infected mothers should not breast-feed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the new born was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.

Fertility

There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.

Patients should be informed that dizziness has been reported during treatment with dolutegravir.

The following side effects have been observed with the use of dolutegravir

System Order Class (SOC) Frequency Side Effects

Immune system disorders Rare: Hypersensitivity; Immune Reconstitution Syndrome (see section 4.4)**

Psychiatric disorders Frequent: Insomnia; abnormal dreams; depression

Rare: Suicidal ideation or suicide attempt (particularly in patients with pre-existing history of depression or psychiatric illness)

Nervous system disorders More Frequent: Headache

Frequent: Dizziness

Gastrointestinal disorders More Frequent: Nausea, diarrhoea

Frequent Vomiting; flatulence; upper abdominal pain; abdominal pain; abdominal discomfort

Hepatobiliary disorders Rare: Hepatitis

Skin and subcutaneous tissue disorders Frequent: Rash; pruritus

General disorders and administration site conditions Frequent: Fatigue

Investigations Frequent Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) elevations; Creatinine phosphokinase (CPK) elevations

**See below under Description of selected side effects

Description of selected side effects

Changes in laboratory biochemistries

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. A mean change from baseline of 9,96 u03bcmol/l was observed after 48 weeks of treatment. Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Symptoms may be the exacerbation of side effects. 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 dolutegravir. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.