Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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).
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.
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.
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.
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.
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.
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.
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).
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 P 450 (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.
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.
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, Cτ = 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% Cτ ↓ 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% Cτ ↑ 13% Tenofovir ↑ AUC ↑ 19% Cmax ↑ 18% Cτ ↑ 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% Cτ ↑ 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% Cτ ↑ 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% Cτ ↑ 88% (inhibition of CYP3A enzymes and P-gp)1 DRV ↔ AUC ↓ 6% Cmax ↓ 2% Cτ ↓ 5% RTV ↔ AUC ↑ 15% Cmax ↔ Cτ ↑ 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% Cτ ↑ 33% Darunavir ↓ AUC ↓ 6% Cmax ↓ 5% Cτ ↓ 12% Ritonavir ↑ AUC ↑ 9% Cmax ↑ 14% Cτ ↑ 7% Etravirine ↔ AUC ↑ 28% Cmax ↑ 18% Cτ ↑ 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% Cτ ↑ 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% Cτ ↑ 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% Cτ ↓ 10% MVC ↔ AUC ↑ 25% Cmax ↑ 1% Cτ ↑ 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% Cτ ↓ 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% Cτ ↓ 41% (induction of CYP3A enzymes)1 | Rifabutin decreased temsavir plasma concentrations. No dose adjustment is necessary. |
| Rifabutin + Ritonavir | Temsavir ↑ AUC ↑ 66% Cmax ↑ 50% Cτ ↑ 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. |
1 Potential mechanism(s) of drug interactions
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 sections 4.4).
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.
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).
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).
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.
The most serious adverse reaction was immune reconstitution inflammatory syndrome (see section 4.4). The most commonly seen treatment emergent adverse reactions were diarrhoea (24%), headache (17%), nausea (15%), rash (12%), abdominal pain (12%), and vomiting (11%).
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</b | 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).
2 Includes central nervous system immune reconstitution inflammatory response and immune reconstitution inflammatory syndrome.
3 Includes abdominal discomfort, abdominal pain and abdominal pain upper.
4 Includes increases in ALT, AST, hepatic enzymes and transaminases.
5 Includes rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic and rash vesicular.
6 Includes pruritus and pruritus generalised.
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 medications 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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