Chemical formula: C₂₅H₂₆N₇O₈P Molecular mass: 583.498 g/mol PubChem compound: 11319217
There are insufficient human data on the use of fostemsavir during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures (see Data).
The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.
Fostemsavir was administered orally to pregnant rats (50, 200, 600 mg/kg/day) and rabbits (25, 50, or 100 mg/kg/day) during Gestation Days 6 to 15 (rat) and 7 to 19 (rabbit). No fetal abnormalities were observed at temsavir exposures of approximately 180 (rat) and 30 (rabbit) times those in humans at the maximum recommended human dose (MRHD). In rabbits, increased embryonic death associated with maternal toxicity was observed at temsavir exposures approximately 60 times those in humans at the MRHD. In a separate rat study conducted at drug exposures approximately 200 times those in humans at the MRHD, fetal abnormalities (cleft palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue) and reductions in fetal body weights occurred in the presence of maternal toxicity.
In a rat pre- and postnatal development study, fostemsavir was administered orally at doses of 10, 50, or 300 mg/kg/day from Gestation Day 6 through Lactation Day 20. Reduced neonatal survival (7 to 14 days after birth) in the absence of other adverse fetal or neonatal effects was observed at maternal temsavir exposures approximately 130 times those in humans at the MRHD. No adverse fetal or neonatal effects were observed at maternal temsavir exposures approximately 35 times those in humans at the MRHD.
In a distribution study in pregnant rats, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) crossed the placenta and were detectable in fetal tissue.
The Centers for Disease Control and Prevention recommends that HIV‑1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
It is not known whether fostemsavir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk (see Data).
Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving fostemsavir.
In a distribution study, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) were excreted in rat milk following a single dose of fostemsavir administered to lactating rats 7 to 9 days postpartum. In the pre- and postnatal development study in rats, temsavir was present in milk at concentrations similar to those measured in maternal plasma, as determined 11 days postpartum. In addition, lactational exposure was associated with reduced offspring survival at maternal temsavir exposures not thought to be clinically relevant.
In a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in transgenic mice, fostemsavir produced no statistically significant increases in tumors over controls. The maximum daily exposures in rats were approximately 5 times (males) and 16 times (females) greater than those in humans at the MRHD.
Fostemsavir was not genotoxic in the bacterial reverse mutation assay (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and rat bone marrow micronucleus test.
Oral administration of fostemsavir had no adverse effects on male or female fertility in rats at exposures approximately 10 times (males) and 186 times (females) of those in humans at the MRHD. At higher exposures (>80 times those in humans at the MRHD) in male rats, decreases in prostate gland/seminal vesicle weights, sperm density/motility, and increased abnormal sperm were observed.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 620 subjects with HIV-1 infection received at least one dose of fostemsavir as part of a controlled clinical trial.
The primary safety assessment of fostemsavir is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatment-experienced adult subjects. In the randomized cohort, 203 subjects received at least one dose of blinded fostemsavir 600 mg twice daily and 69 subjects received placebo in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, all randomized subjects except one received open-label fostemsavir 600 mg twice daily plus an optimized background therapy (OBT). In the nonrandomized cohort, 99 subjects received open-label fostemsavir 600 mg twice daily plus OBT from Day 1 onward.
A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of fostemsavir 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with fostemsavir were mild or moderate in severity. The proportion of subjects who discontinued treatment with fostemsavir due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving fostemsavir). Serious drug reactions occurred in 3% of subjects and included 3 cases of severe immune reconstitution inflammatory syndrome.
Data from the randomized cohort form the basis of the safety assessment of fostemsavir because the presence of significant comorbid illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all grades) reported in ≥2% of subjects in the randomized cohort in the Week 96 analysis are listed below.
Adverse Reactionsa (Grades 1 to 4) Reported in ≥2% of Subjects Receiving Fostemsavir plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis):
| Adverse Reaction | Fostemsavir plus OBT (n=271) |
|---|---|
| Nausea | 10% |
| Diarrhea | 4% |
| Headache | 4% |
| Abdominal painc | 3% |
| Dyspepsia | 3% |
| Fatigued | 3% |
| Rashe | 3% |
| Sleep disturbancef | 3% |
| Immune Reconstitution Inflammatory Syndrome | 2% |
| Somnolence | 2% |
| Vomiting | 2% |
a Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator.
b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving fostemsavir in the open-label phase of the trial.
c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper.
d Includes pooled terms: fatigue and asthenia.
e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic.
f Includes pooled terms: insomnia, sleep deficit, sleep disorder, abnormal dreams.
Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%).
The following adverse reactions occurred in <2% of subjects receiving fostemsavir in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort.
Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic.
Musculoskeletal Disorders: Myalgia.
Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy).
Skin and Subcutaneous Tissue Disorders: Pruritus.
Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥2% of subjects in the randomized cohort of the BRIGHTE trial are presented below.
Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥2% of Subjects in the Randomized Cohort Receiving Fostemsavir plus OBT in the BRIGHTE Trial (Week 96 Analysis):
| Laboratory Parameter Preferred Term | Fostemsavir plus OBT (n=271a) |
|---|---|
| ALT (>5.0 x ULN) | 5% |
| AST (>5.0 x ULN) | 4% |
| Direct bilirubin (>ULN)b | 7% |
| Bilirubin (≥2.6 x ULN) | 3% |
| Cholesterol (≥300 mg/dL)b | 5% |
| Creatinine (>1.8 x ULN or 1.5 x baseline) | 19% |
| Creatine kinase (≥10 x ULN) | 2% |
| Hemoglobin (<9.0 g/dL) | 6% |
| Hyperglycemia (>250 mg/dL) | 4% |
| Lipase (>3.0 x ULN) | 5% |
| LDL cholesterol (≥190 mg/dL) | 4% |
| Neutrophils (≤599 cells/mm³) | 4% |
| Triglycerides (>500 mg/dL) | 5% |
| Urate (>12 mg/dL) | 3% |
ULN = Upper limit of normal.
a Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n=221 for cholesterol and triglycerides, n=216 for LDL cholesterol, and n=268 for all other parameters).
b Grade 3 only (no Grade 4 values reported).
The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively.
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.
Increases in direct (conjugated) bilirubin have been observed following treatment with fostemsavir (Table 2). Cases of clinical significance were uncommon and were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued fostemsavir.
A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn.
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