4.1. Therapeutic indications

Dovato is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine (see section 5.1).

4.2. Posology and method of administration

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

Posology

Adults and adolescents (above 12 years of age weighing at least 40 kg).

The recommended dose of Dovato in adults and adolescents is one 50 mg/300 mg tablet once daily.

Dose adjustments

A separate preparation of dolutegravir is available where a dose adjustment is indicated due to drug-drug interactions (e.g. rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir, see sections 4.4 and 4.5). In these cases the physician should refer to the individual product information for dolutegravir.

Missed doses

If the patient misses a dose of Dovato, the patient should take Dovato 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 Dovato in patients aged 65 years and over. No dose adjustment is necessary (see section 5.2).

Renal impairment

Dovato is not recommended for use in patients with a creatinine clearance < 30 mL/min (see section 5.2). No dose adjustment is required in patients with mild or moderate renal impairment. However, the lamivudine exposure is significantly increased in patients with a creatinine clearance < 50 mL/min (see section 4.4).

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, Dovato should be used with caution in these patients (see section 5.2).

Paediatric population

The safety and efficacy of Dovato in children aged less than 12 years or weighing less than 40 kg have not been established. No data are available.

Method of administration

Oral use.

Dovato can be taken with or without food (see section 5.2).

4.3. Contraindications

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

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

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dovato 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 Dovato or other suspect active substances 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 life style. 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.

Liver disease

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Dovato includes lamivudine, which is active against hepatitis B. Dolutegravir lacks such activity. Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B, since the risk for hepatitis B resistance development is high. If Dovato is used in patients co-infected with hepatitis B an additional antiviral is therefore generally needed. Reference should be made to treatment guidelines.

If Dovato is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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 (often referred to as PCP). 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 reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Liver chemistry 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 chemistries is recommended in patients with hepatitis B and/or C co-infection. (See 'Liver disease' earlier in this section and also see section 4.8).

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues, these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), and metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Some late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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.

Opportunistic infections

Patients should be advised that dolutegravir, lamivudine 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.

Administration in subjects with moderate renal impairment

Patients with a creatinine clearance between 30 and 49 mL/min receiving Dovato may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing Dovato to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Dovato should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with Dovato. Dovato should be discontinued and the individual components should be used to construct the treatment regimen.

Drug interactions

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir (see section 4.5).

Dovato should not be co-administered with polyvalent cation-containing antacids. Polyvalent cation-containing antacids are recommended to be taken 2 hours after or 6 hours before Dovato (see section 4.5).

When taken with food, Dovato and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time. If Dovato 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 Dovato (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of Dovato 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 Dovato. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.

The combination of Dovato with cladribine is not recommended (see section 4.5).

Dovato should not be taken with any other medicinal product containing dolutegravir, lamivudine or emtricitabine, except where a dose adjustment of dolutegravir is indicated due to drug-drug interactions (see section 4.5).

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

No drug interaction studies have been conducted using Dovato. Dovato contains dolutegravir and lamivudine, therefore, any interactions identified for these individually are relevant to Dovato. No clinically significant drug interactions are expected between dolutegravir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir and lamivudine

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Dovato and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may, therefore, increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.

The absorption of dolutegravir is reduced by certain metal cation-containing anti-acid substances and supplements (see Table 1).

Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co‑administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no relevant effect on lamivudine exposure in vivo. Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.

Although lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on lamivudine concentrations.

Effect of dolutegravir and lamivudine on the pharmacokinetics of other medicinal products

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 transporters OCT2 and MATE1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and section 4.3).

In vitro, dolutegravir inhibited the renal uptake organic anion transporters (OAT)1 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.

In vitro, lamivudine was an inhibitor of OCT1 and OCT2; the clinical consequences are not known.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 1.

Interaction table

Interactions between dolutegravir, lamivudine and co-administered medical products are listed in Table 1 (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“). The table should not be considered exhaustive but is representative of the classes studied.

Table 1: Drug Interactions

Medicinal products by therapeutic areas

Interaction geometric mean change (%)

Recommendations concerning co-administration

Antiretroviral medicinal products

Non-nucleoside reverse transcriptase inhibitors

Etravirine without boosted protease inhibitors / Dolutegravir

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 dose of dolutegravir is 50 mg twice daily for patients taking etravirine without boosted protease inhibitors. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the etravirine without boosted protease inhibitor co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Lopinavir+ritonavir+etravirine/ Dolutegravir

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

Lopinavir ↔Ritonavir ↔Etravirine ↔

No dose adjustment is necessary.

Darunavir+ritonavir+etravirine/ Dolutegravir

Dolutegravir ↓   AUC ↓ 25%   Cmax ↓ 12%  C ↓ 36%

Darunavir ↔Ritonavir ↔Etravirine ↔

No dose adjustment is necessary.

Efavirenz/Dolutegravir

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

Efavirenz ↔ (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co‑administered with efavirenz. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the efavirenz co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Nevirapine/Dolutegravir

Dolutegravir ↓

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

The recommended dose of dolutegravir is 50 mg twice daily when co‑administered with nevirapine. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the nevirapine co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Rilpivirine/Dolutegravir

Dolutegravir ↔

AUC ↑ 12%

Cmax ↑ 13%

C ↑ 22%

Rilpivirine ↔

No dose adjustment is necessary.

Nucleoside reverse transcriptase inhibitors (NRTIs)

Tenofovir disoproxil

Emtricitabine, didanosine, stavudine, tenofovir alafenamide, zidovudine

Dolutegravir ↔

AUC ↑ 1%

Cmax ↓ 3%

C ↓ 8%

Tenofovir ↔

Interaction not studied

No dose adjustment is necessary when Dovato is combined with tenofovir, didanosine, stavudine or zidovudine.

Dovato is not recommended for use in combination with emtricitabine containing products, since both lamivudine (in Dovato) and emtricitabine are cytidine analogues (i.e. risk for intracellular interactions), see section 4.4.

Protease inhibitors

Atazanavir/Dolutegravir

Dolutegravir ↑   AUC ↑ 91%  Cmax ↑ 50%  C ↑ 180%

Atazanavir ↔ (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Atazanavir+ ritonavir/ Dolutegravir

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

Atazanavir ↔Ritonavir ↔

No dose adjustment is necessary.

Tipranavir+ritonavir/ Dolutegravir

Dolutegravir ↓   AUC ↓ 59%   Cmax ↓ 47%  C ↓ 76%

Tipranavir ↔Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co administered with tipranavir/ritonavir. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the tipranavir/ritonavir co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Fosamprenavir+ritonavir/ Dolutegravir

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

Fosamprenavir↔

Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

Fosamprenavir/ritonavir decreases dolutegravir concentrations, but based on limited data, did not result in decreased efficacy in Phase III studies. No dose adjustment is necessary.

Lopinavir+ritonavir/ Dolutegravir

Dolutegravir ↔   AUC ↓ 4%  Cmax ↔ 0%   C24 ↓ 6%

Lopinavir ↔Ritonavir ↔

No dose adjustment is necessary.

Darunavir+ritonavir/ Dolutegravir

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

Darunavir ↔Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Other antiviral active substances

Daclatasvir/Dolutegravir

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.

Ledipasvir/Sofosbuvir/ Lamivudine (with abacavir)

Lamivudine ↔

Ledipasvir ↔

Sofosbuvir ↔

No dosage adjustment necessary.

Sofosbuvir/ Velpatasvir/Dolutegravir

Dolutegravir ↔

Sofosbuvir ↔

Velpatasvir↔

No dosage adjustment necessary.

Ribavirin

Interaction not studied.

Clinically significant interaction unlikely.

No dosage adjustment necessary.

Anti-infective products

Trimethoprim/sulfamethoxazole

(Co-trimoxazole)/Lamivudine

(160 mg/800 mg once daily for 5 days/300 mg single dose)

Lamivudine:

AUC ↑ 43%

Cmax ↑ 7%

Trimethoprim:

AUC ↔

Sulfamethoxazole:

AUC ↔

(organic cation transporter inhibition)

No dosage adjustment necessary.

Antimycobacterials

Rifampicin/Dolutegravir

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

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co‑administered with rifampicin. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the rifampicin co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Rifabutin/Dolutegravir

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

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Anticonvulsants

Carbamazepine/Dolutegravir

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

The recommended dose of dolutegravir is 50 mg twice daily when co‑administered with these metabolic inducers. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the co-administration with these metabolic inducers (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Phenobarbital/Dolutegravir

Phenytoin/Dolutegravir

Oxcarbazepine/Dolutegravir

Dolutegravir ↓

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

Antihistamines (histamine H2 receptor antagonists)

Ranitidine

Interaction not studied.

Clinically significant interaction unlikely.

No dosage adjustment necessary.

Cimetidine

Interaction not studied.

Clinically significant interaction unlikely.

No dosage adjustment necessary.

Cytotoxics

Cladribine/Lamivudine

Interaction not studied.

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine.

Concomitant use of Dovato with cladribine is not recommended (see section 4.4).

Miscellaneous

Sorbitol

Sorbitol solution (3.2 g, 10.2 g, 13.4 g)/Lamivudine

Single dose lamivudine oral solution 300 mg.

Lamivudine:

AUC ↓ 14%; 32%; 36%

Cmax ↓ 28%; 52%, 55%.

When possible, avoid chronic coadministration of Dovato with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (eg: xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Potassium channel blockers

Fampridine (also known as dalfampridine)/Dolutegravir

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 Dovato is contraindicated (see section 4.3).

Antacids and supplements

Magnesium/ aluminium‑containing antacids/Dolutegravir

Dolutegravir ↓AUC ↓ 74% Cmax ↓ 72%

(Complex binding to polyvalent ions)

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

Calcium supplements/Dolutegravir(fasted intake)

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

(Complex binding to polyvalent ions)

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

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

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/Dolutegravir(fasted intake)

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

(Complex binding to polyvalent ions)

Multivitamins (containing calcium, iron and magnesium) /Dolutegravir(fasted intake)

Dolutegravir ↓

AUC ↓ 33%

Cmax ↓ 35%

C24 ↓ 32%

(Complex binding to polyvalent ions)

Proton pump inhibitors

Omeprazole

Dolutegravir ↔

No dosage adjustment necessary.

Corticosteroids

Prednisone/Dolutegravir

Dolutegravir ↔

AUC ↑ 11%

Cmax ↑ 6%

C ↑ 17%

No dose adjustment is necessary.

Antidiabetics

Metformin/Dolutegravir

Metformin ↑

Dolutegravir ↔

When co-administered with dolutegravir 50 mg QD:

Metformin   AUC ↑ 79%   Cmax ↑ 66%

When co-administered with dolutegravir 50 mg BID:

Metformin  AUC ↑ 145 %   Cmax ↑ 111%

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

Herbal products

St. John's wort/Dolutegravir

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 dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato for the duration of the St. John's wort co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).

Oral contraceptives

Ethinyl estradiol (EE) and Norgestromin (NGMN)/Dolutegravir

Effect of dolutegravir:

EE ↔   AUC ↑ 3%   Cmax ↓ 1%

Effect of dolutegravir:

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 Dovato.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

There are no or limited amount of data (less than 300 exposed outcomes) from the use of this dual combination in pregnancy.

The safety and efficacy of a dual therapy with dolutegravir + lamivudine has not been studied in pregnancy.

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 over 1000 pregnancies with first trimester dolutegravir treatment and more than 1000 pregnancies with first trimester lamivudine treatment, do not indicate an increased risk of major birth defects with either dolutegravir or lamivudine compared to the background rate or women with HIV. There are no or limited amount of APR data (less than 300 pregnancy exposures) from the use of dolutegravir + lamivudine in pregnant women.

In animal reproductive toxicology studies with dolutegravir, 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. Placental transfer of lamivudine has been shown to occur in humans.

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

Animal studies showed lamivudine may inhibit cellular DNA replication (see section 5.3). The clinical relevance of these findings is unknown.

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3).

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

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.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.

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 or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir or lamivudine on male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Dovato has no or negligible influence on the ability to drive and use machines. Patients should be informed that dizziness and somnolence has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of Dovato 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 frequently reported adverse reactions are headache (3%), diarrhoea (2%), nausea (2%) and insomnia (2%).

The most severe adverse reaction reported with dolutegravir was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions from clinical study and post-marketing experience are listed in Table 2 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), not known (cannot be estimated from the available data).

Table 2: Tabulated summary of adverse reactions to Dovato based on clinical study and post-marketing experience with Dovato and its individual components

Frequency

Adverse reaction

Blood and lymphatic systems disorders:

Uncommon:

neutropenia, anaemia, thrombocytopenia

Very rare:

pure red cell aplasia, sideroblastic anaemia1

Immune system disorders:

Uncommon:

hypersensitivity (see section 4.4), immune reconstitution syndrome (see section 4.4)

Metabolism and nutrition disorders:

Very rare:

lactic acidosis

Psychiatric disorders:

Common:

depression, anxiety, insomnia, abnormal dreams

Uncommon:

suicidal ideation*, suicide attempt*, panic attack*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, somnolence

Very rare:

peripheral neuropathy, paraesthesia

Gastrointestinal disorders:

Very common:

nausea, diarrhoea

Common:

vomiting, flatulence, abdominal pain/ discomfort

Rare:

pancreatitis

Hepatobiliary disorders:

Common:

alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations

Uncommon:

hepatitis

Rare:

acute hepatic failure2, increased bilirubin3

Skin and subcutaneous tissue disorders:

Common:

rash, pruritus, alopecia

Rare:

angioedema

Musculoskeletal and connective tissue disorders:

Common:

arthralgia, muscle disorders (including myalgia)

Rare:

rhabdomyolysis

General disorders and administration site conditions:

Common:

fatigue

Investigations:

Common:

creatine phosphokinase (CPK) elevations, weight increased

Rare:

amylase elevations

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

2 This adverse reaction was identified through post-marketing surveillance for dolutegravir in combination with other ARVs. The frequency category of rare was estimated based on post-marketing reports.

3 In combination with increased transaminases.

Description of selected adverse reactions

Changes in laboratory biochemistries

Dolutegravir has been associated with an increase in serum creatinine occuring in the first week of treatment when administered with other antiretroviral medicinal products. Increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir plus lamivudine and remained stable through 48 weeks. In the pooled GEMINI studies a mean change from baseline of 10.3 µmol/L (range: ‑36.3 µmol/L to 55.7 µmol/L) was observed after 48 weeks of treatment. These changes are linked to the inhibiting effect of dolutegravir on renal tubular transporters of creatinine. The changes are not considered to be clinically relevant and do not reflect a change in glomerular filtration rate.

Co-infection with Hepatitis B or C

In the Phase III studies for the dolutegravir single agent, 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).

Metabolic parameters

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

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

Immune response 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).

Paediatric population

There are no clinical study data on the effects of Dovato in the paediatric population. Individual components have been investigated in adolescents (12 to 17 years).

Based on limited available data with the dolutegravir single entity or lamivudine single entity used in combination with other antiretroviral agents to treat adolescents (12 to 17 years), 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

No specific symptoms or signs have been identified following acute overdose with dolutegravir or lamivudine, apart from those listed as adverse reactions.

There is no specific treatment for an overdose of Dovato. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.