4.1. Therapeutic indications

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 4 weeks of age or older and weighing at least 3 kg.

4.2. Posology and method of administration

Tivicay should be prescribed by physicians experienced in the management of HIV infection.

Posology

Adults

Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class

The recommended dose of dolutegravir is 30 mg (six 5 mg dispersible tablets) orally once daily.

Dolutegravir should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.5.

Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected)

The recommended dose of dolutegravir is 30 mg (six 5 mg dispersible tablets) twice daily.

In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance (see section 5.2).

The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see section 5.1).

Adolescents, children and infants aged 4 weeks and above and weighing at least 3 kg

Patients infected with HIV-1 without resistance to the integrase class

The recommended dose of dolutegravir is determined according to weight and age (see Table 1 and section 5.2).

Table 1 Paediatric dose recommendations for dispersible tablets

Body weight (kg)

Dose

3 to less than 6

5 mg once daily

6 to less than 10

< 6 months

≥ 6 months

10 mg once daily

15 mg once daily

10 to less than 14

20 mg once daily

14 to less than 20

25 mg once daily

20 or greater

30 mg once daily

Alternatively, if preferred the dose may be divided equally into 2 doses, with one dose taken in the morning and one dose taken in the evening (see Table 2 and section 5.2).

Table 2 Alternative paediatric dose recommendations for dispersible tablets

Body weight (kg)

Dose

3 to less than 6

---

6 to less than 10

< 6 months

≥ 6 months

5 mg twice daily

10 mg twice daily

10 to less than 14

10 mg twice daily

14 to less than 20

15 mg twice daily

20 or greater

15 mg twice daily

Patients infected with HIV-1 with resistance to the integrase class

There are insufficient data to recommend a dose for dolutegravir in integrase inhibitor resistant adolescents, children and infants.

Film-coated tablets

Tivicay is available as dispersible tablets for patients aged 4 weeks and above and weighing at least 3 kg, or for patients in whom film-coated tablets are not appropriate. Tivicay is available as film-coated tablets for patients aged 6 years and above and weighing at least 14 kg. Patients can change between dispersible tablets and film-coated tablets. However, the bioavailability of dispersible tablets and film-coated tablets is not comparable, therefore they are not interchangeable on a milligram per milligram basis (see section 5.2). For example, the recommended adult dose for dispersible tablets is 30 mg versus 50 mg for film-coated tablets. Patients changing between dispersible and film-coated tablets should follow the dosing recommendations that are specific for the formulation.

Missed doses

If the patient misses a dose of Tivicay, the patient should take Tivicay as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Elderly

There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2).

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 5.2).

Hepatic impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients (see section 5.2).

Paediatric population

The safety and efficacy of dolutegravir in children aged less than 4 weeks or weighing less than 3 kg have not yet been established. There are insufficient data to recommend a dose for dolutegravir in integrase inhibitor resistant adolescents, children and infants. Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Oral use.

Tivicay can be taken with or without food (see section 5.2). In the presence of integrase class resistance, Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 mutations) (see section 5.2). The dispersible tablets may be dispersed in drinking water, or swallowed whole with drinking water.

When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet(s) should be fully dispersed before swallowing. However, tablets should not be chewed, cut or crushed. The dose of medicine must be given within 30 minutes of preparation. If it has been more than 30 minutes the dose should be washed away and a new dose should be prepared. Comprehensive instructions for dispersing the tablet are provided in the package leaflet (see Step-by-step instructions for use).

If swallowing tablets whole, patients should not swallow more than one tablet at a time, to reduce the risk of choking.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5).

4.4. Special warnings and precautions for use

Integrase class resistance of particular concern

The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see section 5.2).

Hypersensitivity reactions

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect medicinal products 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 or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.

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.

Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8).

Opportunistic infections

Patients should be advised that dolutegravir or any other antiretroviral therapy 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.

Drug interactions

Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/ aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort and certain anti-epileptic medicinal products) (see section 4.5).

When taken with food, Tivicay and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time. If Tivicay is administered under fasting conditions, supplements or multivitamins containing calcium, iron or magnesium are recommended to be taken 2 hours after or 6 hours before Tivicay (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir 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. 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.

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.

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.

Lamivudine and dolutegravir

The two-drug regimen of dolutegravir 50 mg film-coated tablets once daily and lamivudine 300 mg once daily was explored in two large randomized and blinded studies, GEMINI 1 and GEMINI 2 (see section 5.1). This regimen is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Excipients

Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other agents on the pharmacokinetics of dolutegravir

All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.

Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 3).

The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3).

Effect of dolutegravir on the pharmacokinetics of other agents

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. 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 (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. 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 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 3).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) 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.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 3.

Interaction table

Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “C”).

Table 3: Drug Interactions

Medicinal products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

HIV-1 Antiviral Agents

Non-nucleoside Reverse Transcriptase Inhibitors

Etravirine without boosted protease inhibitors

Dolutegravir ↓   AUC ↓ 71%   Cmax ↓ 52%   C ↓ 88%

Etravirine ↔(induction of UGT1A1 and CYP3A enzymes)

Etravirine without boosted protease inhibitors decreased plasma dolutegravir concentration. The recommended adult dose of dolutegravir should be given twice daily when co-administered with etravirine without boosted protease inhibitors. In paediatric patients the weight-based once daily dose should be administered twice daily. Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INI-resistant patients (see further below in table).

Lopinavir/ritonavir + etravirine

Dolutegravir ↔   AUC ↑ 11%   Cmax ↑ 7%   C ↑ 28%LPV ↔RTV ↔

No dose adjustment is necessary.

Darunavir/ritonavir + etravirine

Dolutegravir ↓   AUC ↓ 25%   Cmax ↓ 12%   C ↓ 36%DRV ↔RTV ↔

No dose adjustment is necessary.

Efavirenz

Dolutegravir ↓   AUC ↓ 57%   Cmax ↓ 39%   C ↓ 75%

Efavirenz ↔ (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with efavirenz. In paediatric patients the weight-based once daily dose should be administered twice daily.

In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered (see section 4.4).

Nevirapine

Dolutegravir ↓(Not studied, a similar reduction in exposure as observed with efavirenz is expected, due to induction)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with nevirapine. In paediatric patients the weight-based once daily dose should be administered twice daily.

In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered (see section 4.4).

Rilpivirine

Dolutegravir ↔   AUC ↑ 12%

Cmax ↑ 13%

C ↑ 22%

Rilpivirine ↔

No dose adjustment is necessary.

Nucleoside Reverse Transcriptase Inhibitors

Tenofovir

Dolutegravir ↔   AUC ↑ 1%

Cmax ↓ 3%

C ↓ 8%

Tenofovir ↔

No dose adjustment is necessary.

Protease Inhibitors

Atazanavir

Dolutegravir ↑   AUC ↑ 91%   Cmax ↑ 50%   C ↑ 180%Atazanavir ↔ (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 30 mg twice daily in combination with atazanavir (see section 5.2) due to lack of data.

Atazanavir/ritonavir

Dolutegravir ↑   AUC ↑ 62%   Cmax ↑ 34%   C ↑ 121%

Atazanavir ↔Ritonavir ↔

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 30 mg twice daily in combination with atazanavir (see section 5.2) due to lack of data.

Tipranavir/ritonavir (TPV+RTV)

Dolutegravir ↓   AUC ↓ 59%   Cmax ↓ 47%   C ↓ 76%(induction of UGT1A1 and CYP3A enzymes)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with tipranavir/ritonavir. In paediatric patients the weight-based once daily dose should be administered twice daily.

In the presence of integrase class resistance this combination should be avoided (see section 4.4).

Fosamprenavir/ ritonavir (FPV+RTV)

Dolutegravir ↓   AUC ↓ 35%   Cmax ↓ 24%   C ↓ 49%

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary in the absence of integrase class resistance.

In the presence of integrase class resistance alternative combinations that do not include fosamprenavir/ritonavir should be considered.

Darunavir/ritonavir

Dolutegravir ↓   AUC ↓ 22%   Cmax ↓ 11%   C24 ↓ 38%

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Lopinavir/ritonavir

Dolutegravir ↔   AUC ↓ 4%

Cmax ↔ 0%

C24 ↓ 6%

No dose adjustment is necessary.

Other Antiviral agents

Daclatasvir

Dolutegravir ↔   AUC ↑ 33%   Cmax ↑ 29%   C ↑ 45%

Daclatasvir ↔

Daclatasvir did not change dolutegravir plasma concentration to a clinically relevant extent. Dolutegravir did not change daclatasvir plasma concentration. No dose adjustment is necessary.

Other agents

Potassium channel blocker

Fampridine (also known as dalfampridine)

Fampridine ↑

Co-administration of dolutegravir has the potential to cause seizures due to increased fampridine plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co-administration with dolutegravir is contraindicated.

Anticonvulsants

Carbamazepine

Dolutegravir ↓   AUC ↓ 49%   Cmax ↓ 33%   C ↓ 73%

The recommended adult dose of dolutegravir should be given twice daily when co-administered with carbamazepine. In paediatric patients the weight-based once daily dose should be administered twice daily. Alternatives to carbamazepine should be used where possible for INI resistant patients.

OxcarbazepinePhenytoinPhenobarbital

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with these metabolic inducers. In paediatric patients the weight-based once daily dose should be administered twice daily. Alternative combinations that do not include these metabolic inducers should be used where possible in INI-resistant patients.

Azole anti-fungal agents

Ketoconazole

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Dolutegravir ↔

(Not studied)

No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected.

Herbal products

St. John's wort

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with St. John's wort. In paediatric patients the weight-based once daily dose should be administered twice daily. Alternative combinations that do not include St. John's wort should be used where possible in INI-resistant patients.

Antacids and supplements

Magnesium/ aluminium-containing antacid

Dolutegravir ↓   AUC ↓ 74%   Cmax ↓ 72%

(Complex binding to polyvalent ions)

Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Calcium supplements

(fasted intake)

Dolutegravir ↓   AUC ↓ 39%   Cmax ↓ 37%   C24 ↓ 39%

(Complex binding to polyvalent ions)

When taken with food, Tivicay and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time.

- If Tivicay is taken in a fasted state, such supplements should be taken a minimum 2 hours after or 6 hours before the intake of Tivicay.

The stated reductions in dolutegravir exposure were observed with the intake of dolutegravir and these supplements during fasted conditions. In fed state, the changes in exposure following intake together with calcium or iron supplements were modified by the food effect, resulting in an exposure similar to that obtained with dolutegravir administered in the fasted state.

Iron supplements

(fasted intake)

Dolutegravir ↓   AUC ↓ 54%   Cmax ↓ 57%   C24 ↓ 56%

(Complex binding to polyvalent ions)

Multivitamin

(containing calcium, iron and magnesium)

(fasted intake)

Dolutegravir ↓

AUC ↓ 33%

Cmax ↓ 35%

C24 ↓ 32%

(Complex binding to polyvalent ions)

Corticosteroids

Prednisone

Dolutegravir ↔   AUC ↑ 11%

Cmax ↑ 6%

C ↑ 17%

No dose adjustment is necessary.

Antidiabetics

Metformin

Metformin ↑

When co-administered with dolutegravir 50mg film-coated tablets once daily:

Metformin   AUC ↑ 79%   Cmax ↑ 66%

When co-administered with dolutegravir 50mg film-coated tablets twice daily:

Metformin   AUC ↑ 145 %   Cmax ↑ 111%

A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control. In patients with moderate renal impairment a dose adjustment of metformin should be considered when coadministered with dolutegravir, because of the increased risk for lactic acidosis in patients with moderate renal impairment due to increased metformin concentration (section 4.4).

Antimycobacterials

Rifampicin

Dolutegravir ↓   AUC ↓ 54%   Cmax ↓ 43%   C ↓72%

(induction of UGT1A1 and CYP3A enzymes)

The recommended adult dose of dolutegravir should be given twice daily when co-administered with rifampicin in the absence of integrase class resistance. In paediatric patients the weight-based once daily dose should be administered twice daily.

In the presence of integrase class resistance this combination should be avoided (see section 4.4).

Rifabutin

Dolutegravir ↔   AUC ↓ 5%   Cmax ↑ 16%   C ↓ 30%

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Oral contraceptives

Ethinyl estradiol (EE) and Norelgestromin (NGMN)

Dolutegravir ↔

EE ↔   AUC ↑ 3%   Cmax ↓ 1%

NGMN ↔   AUC ↓ 2%   Cmax ↓ 11%

Dolutegravir had no pharmacodynamic effect on Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and progesterone. No dose adjustment of oral contraceptives is necessary when co-administered with dolutegravir.

Analgesics

Methadone

Dolutegravir ↔

Methadone ↔   AUC ↓ 2%   Cmax ↔ 0%   C ↓ 1%

No dose adjustment is necessary of either agent.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Tivicay can be used during pregnancy if clinically needed.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.

Two large birth outcome surveillance studies (over 14,000 pregnancy outcomes) in Botswana (Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects after dolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%).

Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%) in infants whose mothers were taking dolutegravir at conception (over 9,400 exposures) compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared to women without HIV (0.07%).

Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whose mothers were taking dolutegravir at conception (over 4,800 exposures), as infants of women without HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with first trimester dolutegravir treatment do not indicate an increased risk of major birth defects compared to the background rate or women with HIV.

In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects, were identified (see section 5.3).

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration.

There is insufficient information on the effects of dolutegravir on neonates.

Breast-feeding

Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown. There is insufficient information on the effects of dolutegravir in neonates/infants.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8. Undesirable effects

Summary of the safety profile

The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 4 Adverse Reactions

Blood and lymphatic system disorders

Very rare

Sideroblastic anaemia1

Immune system disorders

Uncommon

Hypersensitivity (see section 4.4)

Uncommon

Immune Reconstitution Syndrome (see section 4.4) 2

Psychiatric disorders

Common

Insomnia

Common

Abnormal dreams

Common

Depression

Common

Anxiety

Uncommon

Panic attack

Uncommon

Suicidal ideation*, suicide attempt*

*particularly in patients with a pre-existing history of depression or psychiatric illness.

Rare

Completed suicide*

*particularly in patients with a pre-existing history of depression or psychiatric illness.

Nervous system disorders

Very common

Headache

Common

Dizziness

Gastrointestinal disorders

Very common

Nausea

Very common

Diarrhoea

Common

Vomiting

Common

Flatulence

Common

Upper abdominal pain

Common

Abdominal pain

Common

Abdominal discomfort

Hepatobiliary disorders

Common

Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) elevations

Uncommon

Hepatitis

Rare

Acute hepatic failure, increased bilirubin3

Skin and subcutaneous tissue disorders

Common

Rash

Common

Pruritus

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia

Uncommon

Myalgia

General disorders and administration site conditions

Common

Fatigue

Investigations

Common

Creatine phosphokinase (CPK) elevations, weight increased

1reversible sideroblastic anaemia has been reported with dolutegravir-containing regimens. The contribution of dolutegravir in these cases is unclear.

2see below under Description of selected adverse reactions.

3in combination with increased transaminases.

Description of selected adverse reactions

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 μmol/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.

Co-infection with Hepatitis B or C

In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see section 4.4).

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Paediatric population

Based on available data from the ongoing P1093 (ING112578) and ODYSSEY (201296) studies in 172 infants, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg), who received the recommended doses of dispersible tablets or film-coated tablets once daily, there were no additional types of adverse reactions beyond those observed in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is currently limited experience with overdosage in dolutegravir.

Limited experience of single higher doses (up to 250 mg film-coated tablets in healthy subjects) revealed no specific symptoms or signs, 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 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.