4.1. Therapeutic indications

Rukobia, in combination with other antiretrovirals, is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen (see sections 4.4 and 5.1).

4.2. Posology and method of administration

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

Posology

The recommended dose is 600 mg of fostemsavir twice daily.

Missed doses

If the patient misses a dose of fostemsavir, the patient should take the missed dose as soon as the patient remembers, unless it is almost time for the next dose. In this case, the missed dose should be skipped and the next dose should be taken according to the regular schedule. The patient should not take a double dose to make up for the forgotten dose.

Elderly

No dosage adjustment is required (see sections 4.4 and 5.2).

Renal impairment

No dosage adjustment is required for patients with renal impairment or those on haemodialysis (see section 5.2).

Hepatic impairment

No dosage adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of fostemsavir in children and adolescents aged less than 18 years have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Method of administration

Oral use.

Fostemsavir can be taken with or without food (see section 5.2). The prolonged-release tablet should be swallowed whole with water, and not chewed, crushed or split.

4.3. Contraindications

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

Co-administration with strong CYP3A inducers including, but not limited to: carbamazepine, phenytoin, mitotane, enzalutamide, rifampicin and St John's wort (see section 4.5).

4.4. Special warnings and precautions for use

Immune reconstitution inflammatory syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (formerly P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, autoimmune hepatitis, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

QTc prolongation

A supratherapeutic dose (at a Cmax approximately 4.2-fold the therapeutic dose) of fostemsavir has been shown to significantly prolong the QTc interval of the electrocardiogram (see section 5.1). Fostemsavir should be used with caution in patients with a history of QT interval prolongation, when co-administered with a medicine with a known risk of Torsade de Pointes (e.g. amiodarone, disopyramide, ibutilide, procainamide, quinidine, or sotalol) or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Patients with hepatitis B or C virus co-infection

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. 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.

Opportunistic infections

Patients should be advised that fostemsavir 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.

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 combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Restricted range of antiviral activity

In vitro data indicate that the antiviral activity of temsavir is restricted to HIV-1 Group M strains. Rukobia should not be used to treat infections due to HIV-1 strains other than those of Group M (see section 5.1).

Within HIV-1 group M, there is considerably reduced antiviral activity against CRF01_AE virus. Available data indicate that this subtype has a natural occurring resistance to temsavir (see section 5.1). It is recommended that Rukobia is not used to treat infections due to HIV-1 Group M subtype CRF01_AE strains.

Interactions with other medicinal products

Co-administration of fostemsavir with elbasvir/grazoprevir is not recommended as increased grazoprevir concentrations may increase the risk of ALT elevations (see section 4.5).

Dose modifications and/or careful titration of dose is recommended for certain statins that are substrates of OATP1B1/3 or BCRP (rosuvastatin, atorvastatin, pitavastatin, simvastatin and fluvastatin) when co-administered with fostemsavir (see section 4.5).

When fostemsavir was co-administered with oral contraceptives, temsavir increased concentrations of ethinyl oestradiol. Doses of oestrogen-based therapies, including oral contraceptives, should not contain more than 30 µg of ethinyl oestradiol per day in patients who are receiving fostemsavir (see section 4.5). Furthermore, caution is advised particularly in patients with additional risk factors for thromboembolic events.

When fostemsavir is co-administered with tenofovir alafenamide (TAF), temsavir is expected to increase plasma concentrations of TAF via inhibition of OATP1B1/3 and/or BCRP. The recommended dose of TAF is 10 mg when co-administered with fostemsavir (see section 4.5).

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

Effect of other medical products on the pharmacokinetics of temsavir

Temsavir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not of organic anion transporters OATP1B1 or OATP1B3. Its biotransformation to two circulating metabolites, BMS-646915 and BMS-930644, is mediated by unidentified esterases (36.1%) and by cytochrome P450 (CYP)3A4 enzyme (21.2%), respectively.

When fostemsavir was co-administered with the strong CYP3A inducer rifampicin, a significant reduction in temsavir plasma concentrations was observed. Significant decreases in temsavir plasma concentrations may also occur when fostemsavir is co-administered with other strong CYP3A inducers, and may result in loss of virologic response (see section 4.3).

Fostemsavir may be co-administered with strong CYP3A4, BCRP and/or P-gp inhibitors (e.g., clarithromycin, itraconazole, posaconazole, and voriconazole) without dose adjustment based on the results of clinical drug interaction studies with cobicistat and ritonavir.

Effect of temsavir on the pharmacokinetics of other medicinal products

In vitro, temsavir inhibited OATP1B1 and OATP1B3 (IC50 = 32 and 16 µM, respectively). Additionally, temsavir and its two metabolites (BMS-646915 and BMS-930644) inhibited BCRP (IC50 = 12, 35, and 3.5 to 6.3 µM, respectively). Based on these data, temsavir is expected to affect the pharmacokinetics of active substances that are substrates of OATP1B1/3 or BCRP (e.g. rosuvastatin, atorvastatin, simvastatin, pitavastatin and fluvastatin). Therefore, dose modifications and/or careful titration of dose is recommended for certain statins.

Interaction table

Selected drug interactions are presented in Table 1. Recommendations are based on either drug interaction studies or predicted interactions based on the expected magnitude of the interaction and potential for serious adverse events or loss of efficacy. (Abbreviations: ↑ = Increase; ↓ =decrease; ↔ = no significant change; AUC=area under the concentration versus time curve; Cmax=maximum observed concentration, C=concentration at the end of dosing interval; *= Using cross-study comparisons to historical pharmacokinetic data).

Table 1: Interactions

Concomitant medicinal product by therapeutic area

Effect on concentration of temsavir or concomitant medicinal product

Recommendation concerning co-administration

HIV-1 Antiviral Agents

Non-nucleoside Reverse Transcriptase Inhibitor

Efavirenz (EFV)

Temsavir ↓

(induction of CYP3A enzymes)1

This interaction has not been studied.Efavirenz is expected to decrease temsavir plasma concentrations. No dose adjustment is necessary.

Etravirine (ETR) without boosted protease inhibitors

Temsavir ↓

AUC ↓ 50%

Cmax ↓ 48%

C ↓ 52%

(induction of CYP3A enzymes)1 ETR ↔

Etravirine decreased temsavir plasma concentrations. No dose adjustment of either medicinal product is necessary.

Nevirapine (NVP)

Temsavir ↓

(induction of CYP3A enzymes)1

This interaction has not been studied.Nevirapine is expected to decrease temsavir plasma concentrations. No dose adjustment is necessary.

Nucleoside Reverse Transcriptase Inhibitor

Tenofovir disoproxil (TDF)

Temsavir ↔

AUC ↔

Cmax ↓ 1%

C ↑ 13%

Tenofovir ↑

AUC ↑ 19%

Cmax ↑ 18%

C ↑ 28%

No dose adjustment of either medicinal product is necessary.

Tenofovir alafenamide (TAF)

TAF ↑

(inhibition of OATP1B1/3 and/or BCRP)

This interaction has not been studied. Temsavir is expected to increase tenofovir alafenamide plasma concentrations. The recommended dose of TAF is 10 mg when co-administered with fostemsavir.

Protease Inhibitor

Atazanavir (ATV)/ritonavir (RTV)

Temsavir ↑

AUC ↑ 54%

Cmax ↑ 68%

C ↑ 57%

(inhibition of CYP3A enzymes and P-gp)1

ATV ↔

RTV ↔

Atazanavir/ritonavir increased temsavir concentrations. No dose adjustment of either medicinal product is necessary.

Darunavir (DRV)/cobicistat

Temsavir ↑

AUC ↑ 97%

Cmax ↑ 79%

C ↑ 124%

(inhibition of CYP3A enzymes, P-gp and/or BCRP)1

Darunavir/cobicistat increased temsavir plasma concentrations. No dose adjustment is necessary.

Darunavir (DRV)/ritonavir

Temsavir ↑

AUC ↑ 63%

Cmax ↑ 52%

C ↑ 88%

(inhibition of CYP3A enzymes and P-gp)1

DRV ↔

AUC ↓ 6%

Cmax ↓ 2%

C ↓ 5%

RTV ↔

AUC ↑ 15%

Cmax ↔

C ↑ 19%

Darunavir/ritonavir increased temsavir plasma concentrations. No dose adjustment is necessary for any medicinal product when co-administered.

Darunavir (DRV)/ritonavir + Etravirine

Temsavir ↑

AUC ↑ 34%

Cmax ↑ 53%

C ↑ 33%

Darunavir ↓

AUC ↓ 6%

Cmax ↓ 5%

C ↓ 12%

Ritonavir ↑

AUC ↑ 9%

Cmax ↑ 14%

C ↑ 7%

Etravirine ↔

AUC ↑ 28%

Cmax ↑ 18%

C ↑ 28%

Darunavir/ritonavir co-administered with etravirine increased temsavir plasma concentrations. No dose adjustment is necessary for any medicinal product when co-administered.

Pharmacokinetic Enhancer

Cobicistat (COBI)

Temsavir ↑

AUC ↑ 93%

Cmax ↑ 71%

C ↑ 136%

(inhibition of CYP3A enzymes, P-gp and/or BCRP)1

Cobicistat increased temsavir plasma concentrations. No dose adjustment is necessary.

Ritonavir

Temsavir ↑

AUC ↑ 45%

Cmax ↑ 53%

C ↑ 44%

(inhibition of CYP3A and P-gp)1

RTV ↔

Ritonavir increased temsavir plasma concentrations. No dose adjustment of either medicinal product is necessary.

Others

Maraviroc (MVC)

Temsavir ↔

Cmax ↑ 13%

AUC ↑ 10%

C ↓ 10%

MVC ↔

AUC ↑ 25%

Cmax ↑ 1%

C ↑ 37%

No dose adjustment of either medicinal product is necessary.

Raltegravir (RAL)

Temsavir ↔*

RAL ↔*

No dose adjustment of either medicinal product is necessary.

Other medicinal products

Buprenorphine/naloxone

Buprenorphine ↔

AUC ↑ 30%

Cmax ↑ 24%

Norbuprenorphine ↔

AUC ↑ 39%

Cmax ↑ 24%

No dose adjustment necessary.

Methadone

Methadone ↔

R-Methadone

AUC ↑ 13%

Cmax ↑ 15%

S-Methadone

AUC ↑ 15%

Cmax ↑ 15%

No dose adjustment necessary.

H2-Receptor Antagonists: Famotidine

Temsavir ↔

AUC ↑ 4%

Cmax ↑ 1%

C ↓ 10%

No dose adjustment is necessary when combined with medicinal products that increase gastric pH.

Oral contraceptives:

Ethinyl estradiol (EE)

Norethindrone acetate (NE)

EE ↑

AUC ↑ 39%

Cmax ↑ 40%

(inhibition of CYP enzymes and/or BCRP)1

NE ↔

AUC ↑ 8%

Cmax ↑ 8%

EE should not exceed 30 µg daily. Caution is advised, particularly in patients with additional risk factors for thromboembolic events (see section 4.4).

No dose adjustment is necessary

Rifabutin

Temsavir ↓

AUC ↓ 30%

Cmax ↓ 27%

C ↓ 41%

(induction of CYP3A enzymes)1

Rifabutin decreased temsavir plasma concentrations. No dose adjustment is necessary.

Rifabutin + Ritonavir

Temsavir ↑

AUC ↑ 66%

Cmax ↑ 50%

C ↑ 158%

Rifabutin co-administered with ritonavir increased temsavir plasma concentrations. No dose adjustment is necessary.

Rifampicin

Temsavir ↓

AUC ↓ 82%

Cmax ↓ 76%

(induction of CYP3A enzymes)

Rifampicin co-administration may lead to loss of virologic response to fostemsavir due to significant decreases in temsavir plasma concentrations caused by strong CYP3A4 induction. Therefore, the concomitant use of fostemsavir and rifampicin is contraindicated.

Although not studied, concomitant use of fostemsavir and other strong CYP3A4 inducers is contraindicated (see section 4.3).

HMG CO-A Reductase Inhibitors:

Rosuvastatin

Atorvastatin

Pitavastatin

Fluvastatin

Simvastatin

Pravastatin

Rosuvastatin ↑

AUC ↑ 69%

Cmax ↑ 78%

(inhibition of OATP1B1/3 and/or BCRP)

Pravastatin ↑

Coadministration of fostemsavir increases rosuvastatin plasma concentrations caused by OATP1B1/3 and/or BCRP inhibition by temsavir. Therefore use the lowest possible starting dose of rosuvastatin with careful monitoring.

Although not studied, use the lowest possible starting dose of other statins that are substrates of OATP1B1/3 and/or BCRP with careful monitoring for HMG-CoA reductase inhibitor-associated adverse reactions.

Although not studied, clinically relevant increases in plasma concentrations of pravastatin are not expected as it is not a substrate of BCRP. No dose adjustment is required.

Hepatitis C virus Direct-Acting Antivirals (HCV DAAs):

Elbasvir/Grazoprevir

Sofosbuvir

Ledipasvir

Velpatasvir

Voxilaprevir

Ombitasvir

Paritaprevir

Dasabuvir

Glecaprevir

Pibrentasvir

Daclatasvir

Grazoprevir ↑

(inhibition of OATP1B1/3)

HCV-DAA ↑

This interaction has not been studied.

Temsavir may increase grazoprevir plasma concentrations to a clinically relevant extent caused by OATP1B1/3 inhibition by temsavir. Co-administration of fostemsavir with elbasvir/grazoprevir is not recommended as increased grazoprevir concentrations may increase the risk of ALT elevations.

Although not studied, temsavir may increase plasma concentrations of other HCV DAAs. No dose adjustment is necessary.

1Potential mechanism(s) of drug interactions

QT prolonging medicinal products

There is no information available on the potential for a pharmacodynamic interaction between fostemsavir and medicinal products that prolong the QTc interval of the ECG. However, based on a study of healthy subjects, in which a supratherapeutic dose of fostemsavir prolonged the QTc interval, fostemsavir should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of fostemsavir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposure levels of temsavir in the range of the recommended human dose (RHD) (see section 5.3). In pregnant rats fostemsavir and/or its metabolites cross the placenta and are distributed to all foetal tissues.

As a precautionary measure, it is preferable to avoid the use of Rukobia during pregnancy.

Breast-feeding

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

It is unknown whether fostemsavir/temsavir are excreted in human milk. Available toxicokinetic data in lactating rats have shown excretion of fostemsavir/temsavir in milk (see section 5.3).

Fertility

There are no data on the effects of fostemsavir on human male or female fertility. Animal studies indicate no effects of fostemsavir on male or female fertility at clinically relevant doses (see section 5.3).

4.7. Effects on ability to drive and use machines

Fostemsavir has a minor influence on the ability to drive and use machines. Patients should be informed that headache, dizziness and somnolence have been reported during treatment with fostemsavir (see section 4.8). The clinical status of the patient and the adverse reaction profile of fostemsavir 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 serious adverse reaction was immune reconstitution inflammatory syndrome (see section 4.4). The most commonly seen adverse reactions were diarrhoea (24%), headache (17%), nausea (15%), rash (12%), abdominal pain (12%), and vomiting (11%).

Tabulated list of adverse reactions

The adverse reactions identified in clinical trials are listed in Table 2 by body system, organ class and 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 2: Tabulated list of adverse reactions

System Organ Class

Frequency1

Adverse Reactions

Immune system disorders

Common

Immune reconstitution inflammatory syndrome2 (see section 4.4)

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Headache

Common

Dizziness, somnolence, dysgeusia

Cardiac disorders

Common

Electrocardiogram QT prolonged (see section 4.4)

Gastrointestinal disorders

Very common

Diarrhoea, nausea, abdominal pain3, vomiting

Common

Dyspepsia, flatulence

Hepatobiliary disorders

Common

Transaminases increased4

Skin and subcutaneous tissue disorders

Very common

Rash5

Common

Pruritus6

Musculoskeletal and connective tissue disorders

Common

Myalgia

General disorders and administration site conditions

Common

Fatigue

Investigations

Common

Blood creatinine increased, blood creatine phosphokinase increased

1 Calculated based on safety data from 570 subjects (n=370 from phase III [BRIGHTE] study at 144 weeks, and n=200 from phase IIb study with mean duration 174 weeks).

2Includes central nervous system immune reconstitution inflammatory response and immune reconstitution inflammatory syndrome.

3Includes abdominal discomfort, abdominal pain and abdominal pain upper.

4Includes increases in ALT, AST, hepatic enzymes and transaminases.

5Includes rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic and rash vesicular.

6Includes pruritus and pruritus generalised.

Description of selected adverse reactions

Changes in laboratory chemistries

Increases in creatine phosphokinase (CPK) were observed following treatment with fostemsavir, which were mainly mild or moderate. These changes were rarely associated with musculoskeletal complaints and are not considered clinically relevant.

Clinically relevant increases in serum creatinine have primarily occurred in patients with identifiable risk factors for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medicinal products known to cause increases in creatinine. A causal association between fostemsavir and elevation in serum creatinine has not been established.

Asymptomatic elevations in creatinine, creatine phosphokinase and liver enzymes were mainly grade 1 or 2 and did not require interruption of treatment.

Increases in direct (conjugated) bilirubin have been observed following treatment with fostemsavir. Cases of clinical significance were uncommon and were confounded by the presence of intercurrent serious comorbid events not related to dosing with study medication (e.g. sepsis, cholangiocarcinoma or other complications of viral hepatitis co-infection). In the remaining reports, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases and resolved on continued fostemsavir.

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

4.9. Overdose

There is no specific treatment for overdose with fostemsavir. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and given appropriate symptomatic treatment. Standard supportive measures should be applied as required, including monitoring of vital signs as well as observation of the clinical status of the patient. As temsavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.