Fostemsavir

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.

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.

Effect on concentration of temsavir or concomitant medicinal product:

Rosuvastatin ↑
AUC ↑ 69%
C_max ↑ 78%

(inhibition of OATP1B1/3 and/or BCRP)

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.

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.

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

Effect on concentration of temsavir or concomitant medicinal product:

EE ↑
AUC ↑ 39%
C_max ↑ 40%

(inhibition of CYP enzymes and/or BCRP)¹

¹ Potential mechanism of drug interactions

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.

Effect on concentration of temsavir or concomitant medicinal product:

TAF ↑

(inhibition of OATP1B1/3 and/or BCRP)

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.

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). 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 fostemsavir 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.

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.

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. 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.

Summary of the safety profile

The most serious adverse reaction was immune reconstitution inflammatory syndrome. The most commonly seen treatment emergent 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 the following table 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).

Tabulated list of adverse reactions:

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.

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 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.