4.1. Therapeutic indications

Biktarvy is indicated for the treatment of human immunodeficiency virus‑1 (HIV‑1) infection in adults and paediatric patients at least 2 years of age and weighing at least 14 kg without present or past evidence of viral resistance to bictegravir or tenofovir (see section 5.1).

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Paediatric patients at least 2 years of age and weighing at least 14 kg to less than 25 kg

One 30 mg/120 mg/15 mg tablet to be taken once daily.

Missed doses

If the patient misses a dose of Biktarvy within 18 hours of the time it is usually taken, the patient should take Biktarvy as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Biktarvy by more than 18 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Biktarvy another tablet should be taken. If a patient vomits more than 1 hour after taking Biktarvy they do not need to take another dose of Biktarvy until the next regularly scheduled dose.

Special populations

Elderly

No dose adjustment of Biktarvy is required in patients aged ≥ 65 years (see sections 4.8 and 5.2).

Hepatic impairment

No dose adjustment of Biktarvy is required in patients with mild (Child‑Pugh Class A) or moderate (Child‑Pugh Class B) hepatic impairment. Biktarvy has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C), therefore Biktarvy is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Renal impairment

No dose adjustment of Biktarvy is required in patients weighing ≥ 35 kg with estimated creatinine clearance (CrCl) ≥ 30 mL/min.

No dose adjustment of Biktarvy is required in adult patients with end stage renal disease (estimated creatinine clearance < 15 mL/minute) who are receiving chronic haemodialysis. However, Biktarvy should generally be avoided and only be used in these patients if the potential benefits are considered to outweigh the potential risks (see sections 4.4 and 5.2). On days of haemodialysis, Biktarvy should be administered after completion of haemodialysis treatment.

Initiation of Biktarvy should be avoided in patients with estimated creatinine clearance ≥15 mL/min and < 30 mL/min, or < 15 mL/min who are not receiving chronic haemodialysis, as the safety of Biktarvy has not been established in these populations (see section 5.2).

No data are available to make dose recommendations in patients weighing < 35 kg with renal impairment or in paediatric patients less than 18 years with end stage renal disease.

Paediatric population

The safety and efficacy of Biktarvy in children less than 2 years of age or weighing less than 14 kg have not yet been established. No data are available.

Method of administration

Oral use

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

Due to the bitter taste, it is recommended that the film‑coated tablets should not be chewed, or crushed. For patients who are unable to swallow the tablet whole, the tablet may be split in half and both halves taken one after the other, ensuring that the full dose is taken immediately.

4.3. Contraindications

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

Co-administration with rifampicin and St. John's wort (Hypericum perforatum) (see section 4.5).

4.4. Special warnings and precautions for use

Patients with HIV and hepatitis B or C virus co-infection

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

There are limited safety and efficacy data for Biktarvy in patients with HIV‑1 and hepatitis C virus (HCV) co-infection.

Biktarvy contains tenofovir alafenamide, which is active against hepatitis B virus (HBV).

Discontinuation of Biktarvy therapy in patients with HIV and HBV co-infection may be associated with severe acute exacerbations of hepatitis. Patients with HIV and HBV co-infection who discontinue Biktarvy should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment.

Liver disease

The safety and efficacy of Biktarvy in patients with significant underlying liver disorders have not been established.

Patients with pre‑existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) 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.

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.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide 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 postnatally 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 events have often been transitory. 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 nucleos(t)ide analogues, who present 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.

Immune Reactivation Syndrome

In patients with HIV and with severe immune deficiency at the time of institution of 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 include 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 reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Opportunistic infections

Patients should be advised that Biktarvy 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 patients with HIV associated diseases.

Osteonecrosis

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

Nephrotoxicity

Post-marketing cases of renal impairment, including acute renal failure and proximal renal tubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapy with Biktarvy and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of Biktarvy should be considered.

Patients with end stage renal disease on chronic haemodialysis

Biktarvy should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh the potential risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in adults with HIV-1 with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 96 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Efficacy was also maintained in the extension phase of the study in which 10 patients switched to Biktarvy for 48 weeks. Although no additional adverse reactions were identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co‑administration of other medicinal products or supplements

Biktarvy should not be co-administered simultaneously with antacids, oral medications or supplements containing magnesium, aluminium, zinc or iron under fasted conditions. Biktarvy should be administered at least 2 hours before, or with food 2 hours after antacids, oral medications or supplements containing magnesium, and/or aluminium. Biktarvy should be administered at least 2 hours before iron and/or zinc supplements, or taken together with food at any time (see section 4.5).

In pregnant patients, dosage adjustments are recommended for co-administration of polyvalent cation-containing antacids, oral medications or supplements (see section 4.5).

Some medicinal products are not recommended for co‑administration with Biktarvy: atazanavir, carbamazepine, ciclosporin (IV or oral use), oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, or sucralfate.

Biktarvy should not be co‑administered with other antiretroviral medicinal products.

Paediatric population

Reductions in bone mineral density (BMD ≥ 4%) of the spine and total body less head (TBLH) have been reported in patients aged between 3 to < 12 years who received tenofovir alafenamide‑containing products for 48 weeks (see section 4.8). The long-term effects of changes in BMD on the growing bone, including the risk of fracture, are uncertain. A multidisciplinary approach is recommended to decide the appropriate monitoring during treatment.

Excipients

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

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

Interaction studies have only been performed in adults.

Biktarvy should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection.

Bictegravir

Bictegravir is a substrate of CYP3A and UGT1A1. Co‑administration of bictegravir and medicinal products that potently induce both CYP3A and UGT1A1, such as rifampicin or St. John's wort, may significantly decrease plasma concentrations of bictegravir, which may result in a loss of therapeutic effect of Biktarvy and development of resistance, therefore co‑administration is contraindicated (see section 4.3). Co‑administration of bictegravir with medicinal products that potently inhibit both CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations of bictegravir, therefore co‑administration is not recommended.

Bictegravir is both a P‑gp and a BCRP substrate. The clinical relevance of this feature is not established. Therefore, caution is recommended when bictegravir is combined with medicinal products known to inhibit P‑gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone, glecaprevir/pibrentasvir) (see also table below).

Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Co‑administration of Biktarvy with the OCT2 and MATE1 substrate metformin did not result in a clinically significant increase in metformin exposure. Biktarvy may be co-administered with substrates of OCT2 and MATE1.

Bictegravir is not an inhibitor or inducer of CYP in vivo.

Emtricitabine

In vitro and clinical pharmacokinetic drug‑drug interaction studies have shown that the potential for CYP‑mediated interactions involving emtricitabine with other medicinal products is low. Co‑administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co‑administered medicinal product. Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P‑gp) and breast cancer resistance protein (BCRP). Co‑administration of Biktarvy with medicinal products that strongly affect P‑gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medicinal products that induce P‑gp activity (e.g. rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Biktarvy and development of resistance. Co‑administration of Biktarvy with other medicinal products that inhibit P‑gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.

Other interactions

Interactions between Biktarvy or its individual component(s) and co‑administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”; all No Effect Boundaries are 70%‑143%).

Table 1: Interactions between Biktarvy or its individual component(s) and other medicinal products

Medicinal product by therapeutic areas/possible mechanism of interaction

Effects on medicinal product levels.

Mean percent change in AUC, Cmax, Cmin

Recommendation concerning co‑administration with Biktarvy

HERBAL PRODUCTS

St. John's wort (Hypericum perforatum)

(Induction of CYP3A, UGT1A1, and P‑gp)

Interaction not studied with any of the components of Biktarvy.

Co‑administration may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration with St. John's wort is contraindicated, due to the effect of St. John's wort on the bictegravir component of Biktarvy.

ANTI‑INFECTIVES

Antimycobacterials

Rifampicin (600 mg once daily),

Bictegravir1

(Induction of CYP3A, UGT1A1, and P‑gp)

Bictegravir:

AUC: ↓ 75%

Cmax: ↓ 28%

Interaction not studied with tenofovir alafenamide.

Co‑administration of rifampicin may decrease tenofovir alafenamide plasma concentrations.

Co‑administration is contraindicated due to the effect of rifampicin on the bictegravir component of Biktarvy.

Rifabutin (300 mg once daily),

Bictegravir1

(Induction of CYP3A and P‑gp)

Bictegravir:

AUC: ↓ 38%

Cmin: ↓ 56%

Cmax: ↓ 20%

Interaction not studied with tenofovir alafenamide.

Co‑administration of rifabutin may decrease tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended due to the expected decrease of tenofovir alafenamide.

Rifapentine

(Induction of CYP3A and P‑gp)

Interaction not studied with any of the components of Biktarvy.

Co‑administration of rifapentine may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended.

HIV‑1 antiviral agents

Atazanavir (300 mg once daily), Cobicistat (150 mg once daily), Bictegravir1

(Inhibition of CYP3A, UGT1A1, and P‑gp/BCRP)

Bictegravir:

AUC: ↑ 306%

Cmax: ↔

Co‑administration is not recommended.

Atazanavir (400 mg once daily), Bictegravir1

(Inhibition of CYP3A and UGT1A1)

Bictegravir:

AUC: ↑ 315%

Cmax: ↔

Hepatitis C virus antiviral agents

Ledipasvir/Sofosbuvir (90 mg/400 mg once daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide2

Bictegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Ledipasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sofosbuvir:

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS‑331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Sofosbuvir/Velpatasvir/ Voxilaprevir (400/100/100 + 100 mg3 once daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide

(Inhibition of P‑gp/BCRP)

Bictegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↑ 57%

Cmax: ↑ 28%

Sofosbuvir:

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS‑331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

Velpatasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Voxilaprevir:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Antifungals

Voriconazole (300 mg twice daily), Bictegravir1

(Inhibition of CYP3A)

Bictegravir:

AUC: ↑ 61%

Cmax: ↔

No dose adjustment is required upon co‑administration.

Itraconazole

Posaconazole

(Inhibition of P‑gp/BCRP)

Interaction not studied with any of the components of Biktarvy.

Co‑administration of itraconazole or posaconazole may increase bictegravir plasma concentrations.

Macrolides

Azithromycin

Clarithromycin

(Inhibition of P‑gp)

Interaction not studied.

Co-administration of azithromycin or clarithromycin may increase bictegravir plasma concentrations.

Caution is recommended due to the potential effect of these medicinal products on the bictegravir component of Biktarvy.

ANTICONVULSANTS

Carbamazepine (titrated from 100 mg to 300 mg twice a day), Emtricitabine/Tenofovir alafenamide4

(Induction of CYP3A, UGT1A1, and P‑gp)

Tenofovir alafenamide:

AUC: ↓ 54%

Cmax: ↓ 57%

Interaction not studied with bictegravir.

Co‑administration of carbamazepine may decrease bictegravir plasma concentrations.

Co‑administration is not recommended.

Oxcarbazepine

Phenobarbital

Phenytoin

(Induction of CYP3A, UGT1A1, and P‑gp)

Interaction not studied with any of the components of Biktarvy.

Co‑administration of oxcarbazepine, phenobarbital, or phenytoin may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended.

ANTACIDS, SUPPLEMENTS AND BUFFERED MEDICINES

Magnesium/aluminium-containing antacid suspension (20 mL single dose5), Bictegravir

(Chelation with polyvalent cations)

Bictegravir (antacid suspension 2 hours prior, fasted):

AUC: ↓ 52%

Cmax: ↓ 58%

Bictegravir (antacid suspension after 2 hours, fasted):

AUC: ↔

Cmax: ↔

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 79%

Cmax: ↓ 80%

Bictegravir (simultaneous administration with food):

AUC: ↓ 47%

Cmax: ↓ 49%

For non-pregnant patients:

Biktarvy should not be taken simultaneously with antacids or supplements containing magnesium and/or aluminium due to the expected substantial decrease of bictegravir exposure (see section 4.4).

Biktarvy should be administered at least 2 hours before, or with food 2 hours after antacids or supplements containing magnesium and/or aluminium.

For pregnant patients:

Biktarvy should be administered at least 2 hours before or 6 hours after taking antacids or supplements containing aluminium and/or magnesium without regard to food.

Zinc

(Chelation with polyvalent cations)

Interaction not studied with any of the components of Biktarvy.

Co‑administration may decrease bictegravir plasma concentrations.

For non-pregnant patients:

Biktarvy should be administered at least 2 hours before taking oral medications or supplements containing zinc, or taken together with food at any time.

For pregnant patients:

Biktarvy should be administered at least 2 hours before or 6 hours after taking oral medications or supplements containing zinc.

Alternatively, Biktarvy and oral medications or supplements containing zinc can be taken together with food at any time.

Ferrous fumarate (324 mg single dose), Bictegravir

(Chelation with polyvalent cations)

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 63%

Cmax: ↓ 71%

Bictegravir (simultaneous administration with food):

AUC: ↔

Cmax: ↓ 25%

For non-pregnant patients:

Biktarvy should be administered at least 2 hours before oral medications or supplements containing iron, or taken together with food at any time.

For pregnant patients:

Biktarvy should be administered at least 2 hours before or 6 hours after taking oral medications or supplements containing iron. Alternatively, Biktarvy and oral medications or supplements containing iron can be taken together with food at any time.

Calcium carbonate (1,200 mg single dose), Bictegravir

(Chelation with polyvalent cations)

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 33%

Cmax: ↓ 42%

Bictegravir (simultaneous administration with food):

AUC: ↔

Cmax: ↔

For non-pregnant patients:

Biktarvy and calcium-containing oral medications or supplements can be taken together, without regard to food.

For pregnant patients:

Biktarvy should be administered at least 2 hours before or 6 hours after taking oral medications or supplements containing calcium. Alternatively, Biktarvy and oral medications or supplements containing calcium can be taken together with food at any time.

Sucralfate

(Chelation with polyvalent cations)

Interaction not studied with any of the components of Biktarvy.

Co‑administration may decrease bictegravir plasma concentrations.

Co‑administration not recommended.

ANTIDEPRESSANTS

Sertraline (50 mg single dose), Tenofovir alafenamide6

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Sertraline:

AUC: ↔

Cmax: ↔

No interaction is expected with bictegravir and emtricitabine.

No dose adjustment is required upon co‑administration.

IMMUNOSUPPRESSANTS

Ciclosporin (IV or oral use)

(P‑gp inhibition)

Interaction not studied with any of the components of Biktarvy.

Co-administration of ciclosporin (IV or oral use) is expected to increase plasma concentrations of both bictegravir and tenofovir alafenamide.

Co‑administration of ciclosporin (IV or oral use) is not recommended. If the combination is needed, clinical and biological monitoring, notably renal function, is recommended.

ORAL ANTI-DIABETICS

Metformin (500 mg twice daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide

(Inhibition of OCT2/MATE1)

Metformin:

AUC: ↑ 39%

Cmin: ↑ 36%

Cmax: ↔

No dose adjustment is required upon co‑administration in patients with normal renal function.

In patients with moderate renal impairment, close monitoring should be considered when starting co‑administration of bictegravir with metformin, due to the increased risk for lactic acidosis in these patients. A dose adjustment of metformin should be considered if required.

ORAL CONTRACEPTIVES

Norgestimate (0.180/0.215/0.250 mg once daily)/ Ethinylestradiol (0.025 mg once daily), Bictegravir1

Norelgestromin:

AUC: ↔

Cmin: ↔

Cmax: ↔

Norgestrel:

AUC: ↔

Cmin: ↔

Cmax: ↔

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Norgestimate (0.180/0.215/0.250 mg once daily), Ethinylestradiol (0.025 mg once daily), Emtricitabine/Tenofovir alafenamide4

SEDATIVES/HYPNOTICS

Midazolam (2 mg, oral syrup, single dose), Bictegravir/Emtricitabine/ Tenofovir alafenamide

Midazolam:

AUC: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

1 This study was conducted using bictegravir 75 mg single dose.

2 This study was conducted using bictegravir/emtricitabine/tenofovir alafenamide 75/200/25 mg once daily.

3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in patients with HCV.

4 This study was conducted using emtricitabine/tenofovir alafenamide 200/25 mg once daily.

5 Maximum strength antacid contained 80 mg aluminium hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone per mL.

6 This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 150/150/200/10 mg once daily.

Based on drug interaction studies conducted with Biktarvy or the components of Biktarvy, no clinically significant drug interactions are expected with: amlodipine, atorvastatin, buprenorphine, drospirenone, famciclovir, famotidine, fluticasone, methadone, naloxone, norbuprenorphine, omeprazole or rosuvastatin.

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative or foeto/neonatal toxicity associated with emtricitabine or tenofovir alafenamide. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity associated with bictegravir.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development. Studies of bictegravir and tenofovir alafenamide, administered separately, in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development (see section 5.3).

In a study performed in pregnant women receiving Biktarvy, exposures of bictegravir, emtricitabine and tenofovir alafenamide were lower during pregnancy (see section 5.2).

Therefore, Biktarvy may be used during pregnancy if the potential benefit justifies the potential risk to the foetus. Moreover, viral load should all the more be monitored closely in accordance with established treatment guidelines.

Breast‑feeding

It is not known whether bictegravir is excreted in human milk. Emtricitabine is excreted in human milk. Based on published data, tenofovir alafenamide is excreted in human milk at low levels. The relative infant dose (RID) is estimated to be below 0.1% of the maternal weight-adjusted dose. In animal studies, bictegravir was detected in the plasma of nursing rat pups likely due to the presence of bictegravir in milk, without effects on nursing pups.

There is insufficient information on the effects of all the components of Biktarvy in newborns/infants, therefore Biktarvy should not be used during breast‑feeding.

In order to avoid transmission of HIV to the infant it is recommended that women with HIV do not breast‑feed their infants.

Fertility

No human data on the effect of Biktarvy on fertility are available. Animal studies indicate no effects of bictegravir, emtricitabine or tenofovir alafenamide on mating or fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Biktarvy may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with the components of Biktarvy (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

In clinical studies of treatment-naïve patients receiving Biktarvy, the most frequently reported adverse reactions in the double-blind phase (Week 144) were headache (5%), diarrhoea (5%) and nausea (4%).

Tabulated list of adverse reactions

The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with Biktarvy and from post-marketing experience. The adverse reactions in Table 2 are listed by system organ class and frequency. Frequencies are defined as follows: common (≥ 1/100 to < 1/10) uncommon (≥ 1/1 000 to < 1/100) and rare (≥ 1/10 000 to < 1/1 000).

Table 2: Tabulated list of adverse reactions1

Frequency

Adverse reaction

Blood and lymphatic system disorders

Uncommon:

anaemia2

Psychiatric disorders

Common:

depression, abnormal dreams

Uncommon:

suicidal ideation, suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness), anxiety, sleep disorders

Nervous system disorders

Common:

headache, dizziness

Gastrointestinal disorders

Common:

diarrhoea, nausea

Uncommon:

vomiting, abdominal pain, dyspepsia, flatulence

Hepatobiliary disorders

Uncommon:

hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Uncommon:

angioedema3,4, rash, pruritus, urticaria4

Rare:

Stevens-Johnson syndrome5

Musculoskeletal and connective tissue disorders

Uncommon:

arthralgia

General disorders and administration site conditions

Common:

fatigue

Investigations

Common:

weight increased

1 With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adverse reactions were identified from Biktarvy clinical studies. The frequencies were derived from Phase 3 Biktarvy clinical studies in treatment‑naïve patients through 144 weeks (GS‑US‑380‑1489 and GS‑US‑380‑1490).

2 This adverse reaction was not observed in the clinical studies of emtricitabine + tenofovir alafenamide‑containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.

3 This adverse reaction was identified through post-marketing surveillance for emtricitabine‑containing products.

4 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products.

5 This adverse reaction was identified through post-marketing surveillance for Biktarvy. The frequency has been calculated using 3/X, where X represent the cumulative number of participants exposed to Biktarvy in clinical trials (N=3963).

Description of selected adverse reactions

Metabolic parameters

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

Immune Reactivation Syndrome

In patients with HIV and with severe immune deficiency at the time of initiation of 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).

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).

Changes in serum creatinine

Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine, however these changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 144. In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, median (Q1, Q3) serum creatinine increased by 0.11 (0.03, 0.19) mg/dL (9.7 [2.7, 16.8] µmol/L), 0.11 (0.04, 0.19) mg/dL (9.7 [3.5, 16.8] µmol/L), and 0.12 (0.06, 0.21) mg/dL (10.6 [5.3, 18.6] μmol/L) from baseline to Week 144 in the Biktarvy, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively. There were no discontinuations due to renal adverse reactions through Week 144 in patients administered Biktarvy in clinical studies.

Changes in bilirubin

In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, total bilirubin increases were observed in 17% of treatment-naïve patients administered Biktarvy through Week 144. Increases were primarily Grade 1 (12%) and Grade 2 (4%) (≥1.0 to 2.5 x Upper Limit of Normal [ULN]), and were not associated with hepatic adverse reactions or other liver related laboratory abnormalities. Five patients administered Biktarvy (1%) had grade 3 bilirubin increases that were not considered related to study drug. There were no discontinuations due to hepatic adverse reactions through Week 144 in Biktarvy clinical studies.

Paediatric population

The safety of Biktarvy was evaluated in 50 adolescents with HIV-1 aged 12 to < 18 years and weighing ≥ 35 kg through Week 96 (48-week main phase and 48-week extension), in 50 children aged 6 to < 12 years and weighing ≥ 25 kg through Week 96 (48-week main phase and 48-week extension), and in 22 children ≥ 2 years of age and weighing ≥ 14 to < 25 kg through Week 24 in an open‑label clinical study (GS-US-380-1474). In this study, no new adverse reactions have been observed in paediatric participants aged 2 years and older with HIV-1 as compared to adult participants with HIV-1. Bone mineral density data were not collected in this study. Reductions in BMD of the spine and of the TBLH ≥ 4% have been reported in paediatric patients receiving other tenofovir alafenamide containing products for 48 weeks (see section 4.4).

Other special populations

Patients with HIV and hepatitis B virus co-infection

In 16 adults with HIV and HBV co-infection who were administered Biktarvy (8 adults who were HIV/HBV treatment‑naïve in Study GS‑US‑380‑1490; 8 adults with HIV/HBV who were virologically suppressed in Study GS‑US‑380‑1878), the safety profile of Biktarvy was similar to that in patients with HIV‑1 monoinfection (see section 5.1).

Elderly

Studies GS‑US‑380‑1844, GS‑US‑380‑1878 and the dedicated Study GS‑US‑380‑4449 in patients ≥ 65 years old (evaluation of 86 participants with virologically-suppressed HIV‑1) included 111 patients aged ≥ 65 years who received Biktarvy. In these patients, no differences in the safety profile of Biktarvy were observed.

Patients with virologically suppressed HIV-1

No additional adverse reactions to Biktarvy were identified through Week 48 in a controlled clinical study (GS-US-380-4030) of participants with virologically-suppressed HIV-1 who switched from dolutegravir plus either emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate, to Biktarvy (N=284).

Patients with renal impairment

The safety of emtricitabine + tenofovir alafenamide was evaluated in a single arm, open-label clinical study (GS-US-292-1825), in which 55 patients with virologically-suppressed HIV-1 with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis received emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet for 96 weeks. In an extension phase of Study GS‑US‑292‑1825, 10 patients switched to Biktarvy for 48 weeks. No additional adverse reactions were identified in patients with end stage renal disease on chronic haemodialysis in this study (see sections 4.4 and 5.2).

Pregnancy

Biktarvy was evaluated in a clinical study of 33 HIV-1 infected virologically suppressed (HIV-1 RNA < 50 copies/mL) pregnant adults administered 50 mg/200 mg/25 mg Biktarvy once daily from the second or third trimester through postpartum. There were no new safety findings compared to the known safety profile of Biktarvy in HIV-1 infected adults.

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 the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with Biktarvy consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

There is no specific antidote for overdose with Biktarvy. As bictegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis. Emtricitabine can be removed by haemodialysis, which removes approximately 30% of the emtricitabine dose over a 3‑hour dialysis period starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.