Dolutegravir

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with St. John’s wort. In paediatric patients the weightbased 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.

Interaction – Geometric mean change (%): Dolutegravir ↓

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

No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients.

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, iron supplements or multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Interaction – Geometric mean change (%):

Calcium supplements: Dolutegravir ↓, AUC ↓39%, C_max ↓37%, C₂₄ ↓39% (complex binding to polyvalent ions)

Iron supplements: Dolutegravir ↓, AUC ↓54%, C_max ↓57%, C₂₄ ↓56% (complex binding to polyvalent ions)

Multivitamin: Dolutegravir ↓, AUC ↓33%, C_max ↓35%, C₂₄ ↓32%

No dose adjustment is necessary. Dolutegravir should not be dosed higher than 50 mg twice daily in combination with atazanavir due to lack of data.

Interaction – Geometric mean change (%):

Dolutegravir ↑, AUC: ↑91%, C_max: ↑50%, C_τ: ↑180%

Atazanavir ↔ (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine. In paediatric patients the weightbased once daily dose should be administered twice daily. Alternatives to carbamazepine should be used where possible for INI resistant patients.

Interaction – Geometric mean change (%): Dolutegravir ↓, AUC ↓49%, C_max ↓33%, C_τ ↓73%

The recommended adult dose of dolutegravir is 50 mg 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.

Interaction – Geometric mean change (%):

Dolutegravir ↓, AUC: ↓57%, C_max: ↓39%, C_τ: ↓75%

Efavirenz ↔ (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

Etravirine without boosted protease inhibitors decreased plasma dolutegravir concentration. The recommended adult dose of dolutegravir is 50 mg 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 coadministration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INIresistant patients.

Geometric mean change (%):

Dolutegravir ↓, AUC: ↓71%, C_max: ↓52%, C_τ: ↓88%

Etravirine ↔

(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.

Interaction – Geometric mean change (%): Dolutegravir ↓, AUC ↓35%, C_max ↓24%, C_τ ↓49%

(induction of UGT1A1 and CYP3A enzymes)

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. 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.

Interaction – Geometric mean change (%):

When co-administered with dolutegravir 50mg once daily: Metformin ↑, AUC ↑ 79%, C_max ↑ 66%

When co-administered with dolutegravir 50mg twice daily: Metformin ↑, AUC ↑ 145%, C_max ↑ 111%

The recommended adult dose of dolutegravir is 50 mg 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.

Interaction – Geometric mean change (%): Dolutegravir ↓

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

The recommended adult dose of dolutegravir is 50 mg 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 INIresistant patients.

Interaction – Geometric mean change (%): 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 is 50 mg 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.

Interaction – Geometric mean change (%): Dolutegravir ↓, AUC ↓54%, C_max ↓43%, C_τ ↓72% (induction of UGT1A1 and CYP3A enzymes)

The recommended adult dose of dolutegravir is 50 mg 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.

Interaction – Geometric mean change (%): Dolutegravir ↓, AUC ↓59%, C_max ↓47%, C_τ ↓76%

(induction of UGT1A1 and CYP3A enzymes)

Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravircontaining regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception.

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%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If a 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.

Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.

In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects, were identified.

More than 1000 outcomes from exposure during second and third trimester of pregnancy indicate no evidence of increased risk of foetal/neonatal toxicity. Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.

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.

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.

Women of childbearing potential

Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of effective contraceptive measures.

If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir should be discussed with the patient.

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 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.

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. 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).

Adverse Reactions:

^** see below under Description of selected adverse reactions.
^*** in 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.

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.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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 film-coated tablets or dispersible tablets once daily, there were no additional types of adverse reactions beyond those observed in the adult population.