Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
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).
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 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.
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).
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.
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 antiepileptic medicinal products) (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.
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.
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.
The two-drug regimen of dolutegravir 50 mg 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.
Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium free’.
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).
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 2.
Interactions between dolutegravir and co-administered medicinal products are listed in Table 2 (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 "Cτ").
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% Cτ ↓ 88% Etravirine ↔ (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 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% Cτ ↑ 28% LPV ↔ RTV ↔ | No dose adjustment is necessary. |
| Darunavir/ritonavir + etravirine | Dolutegravir ↓ AUC ↓ 25% Cmax ↓ 12% Cτ ↓ 36% DRV ↔ RTV ↔ | No dose adjustment is necessary. |
| Efavirenz | Dolutegravir ↓ AUC ↓ 57% Cmax ↓ 39% Cτ ↓ 75% Efavirenz ↔ (historical controls) (induction of UGT1A1 and CYP3A enzymes) | 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 (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 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 (see section 4.4). |
| Rilpivirine | Dolutegravir ↔ AUC ↑ 12% Cmax ↑ 13% Cτ ↑ 22% Rilpivirine ↔ | No dose adjustment is necessary. |
| Nucleoside Reverse Transcriptase Inhibitors | ||
| Tenofovir | Dolutegravir ↔ AUC ↑ 1% Cmax ↓ 3% Cτ ↓ 8% Tenofovir ↔ | No dose adjustment is necessary. |
| Protease Inhibitors | ||
| Atazanavir | Dolutegravir ↑ AUC ↑ 91% Cmax ↑ 50% Cτ ↑ 180% Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes) | No dose adjustment is necessary. Tivicay should not be dosed higher than 50 mg twice daily in combination with atazanavir (see section 5.2) due to lack of data. |
| Atazanavir/ritonavir | Dolutegravir ↑ AUC ↑ 62% Cmax ↑ 34% Cτ ↑ 121% Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes) | No dose adjustment is necessary. Tivicay should not be dosed higher than 50 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% Cτ ↓ 76% (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 (see section 4.4). |
| Fosamprenavir/ ritonavir (FPV+RTV) | Dolutegravir ↓ AUC ↓ 35% Cmax ↓ 24% Cτ ↓ 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% Cτ ↑ 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% Cτ ↓ 73% | The recommended adult dose of dolutegravir is 50 mg 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. |
| Oxcarbazepine Phenytoin Phenobarbital | 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 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 is 50 mg 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 | Dolutegravir ↓ AUC ↓ 39% Cmax ↓ 37% C24 ↓ 39% (Complex binding to polyvalent ions) | 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). |
| Iron supplements | Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 57% C24 ↓ 56% (Complex binding to polyvalent ions) | |
| Multivitamin | Dolutegravir ↓ AUC ↓ 33% Cmax ↓ 35% C24 ↓ 32% (Complex binding to polyvalent ions) | |
| Corticosteroids | ||
| Prednisone | Dolutegravir ↔ AUC ↑ 11% Cmax ↑ 6% Cτ ↑ 17% | No dose adjustment is necessary. |
| Antidiabetics | ||
| Metformin | Metformin ↑ When co-administered with dolutegravir 50mg once daily: Metformin AUC ↑ 79% Cmax ↑ 66% When co-administered with dolutegravir 50mg 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% Cτ ↓72% (induction of UGT1A1 and CYP3A enzymes) | 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 (see section 4.4). |
| Rifabutin | Dolutegravir ↔ AUC ↓ 5% Cmax ↑ 16% Cτ ↓ 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% Cτ ↓ 1% | No dose adjustment is necessary of either agent. |
Interaction studies have only been performed in adults.
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.
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 (see section 5.3).
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.
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).
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.
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%).
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:
| Immune system disorders | Uncommon | Hypersensitivity (see section 4.4) |
| Uncommon | Immune Reconstitution Syndrome (see section 4.4)** | |
| 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 bilirubin*** | |
| 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 |
** see below under Description of selected adverse reactions.
*** in combination with increased transaminases
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.
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).
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).
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
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.
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 the national reporting system listed in Appendix V.
Not applicable.
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