SUMMARY

• There are limited data on the use of UPTRAVI in pregnant women. As a precautionary measure, it is preferable to avoid the use of UPTRAVI during pregnancy, unless clearly needed to do so. It is also unknown whether UPTRAVI or its metabolites are excreted in human milk. In rats, UPTRAVI or its metabolites are excreted in the milk. Breastfeeding is not recommended during treatment with UPTRAVI.¹
• In preclinical reproductive toxicity studies, UPTRAVI was not teratogenic in rats or rabbits and had no effect on fertility of male and female rats. In the rat pre and postnatal development study, UPTRAVI did not affect maternal and pup reproductive function. In addition, UPTRAVI was not genotoxic on the basis of the overall evidence of conducted genotoxicity  studies.²
• In clinical trials with UPTRAVI, participating women of childbearing potential must have a negative pregnancy test before inclusion in the study and agree to perform monthly pregnancy tests up to 30 days after last dose of the study drug and agree to use reliable contraception from screening up to 1 month following discontinuation of the study treatment. Birth control is not required in male study participants.²
• In a search of the internal global safety database (cutoff date: 20 December 2023), a total of 96 confirmed pregnancies in UPTRAVI-treated patients have been reported, including 20 from interventional clinical trials.³ Details are provided in this letter. There are currently no data indicating that UPTRAVI causes malformations in fetuses and the expected exposure to a pregnant woman or embryo via sperm is negligible.²
• Please note that this document does not contain any reference to the local prescribing information. For complete prescribing recommendations and information on pregnancy, child-bearing potential, contraception, and fertility about UPTRAVI in your country, please refer to your local product information.

CLINICAL DATA

Information From Pre-Clinical Studies

UPTRAVI was not teratogenic in rats or rabbits and had no effect on fertility of male and female rats in the reproductive toxicity studies. In the rat pre and postnatal development study, UPTRAVI did not affect maternal and pup reproductive function. Drug- related material has been detected in milk of lactating rats, indicating transfer of UPTRAVI or its metabolites to milk.²

UPTRAVI was not genotoxic on the basis of the overall evidence of conducted genotoxicity studies.²

Information From Internal Safety Database

In clinical trials with UPTRAVI, participating women of childbearing potential must have a negative pregnancy test before inclusion in the study and agree to perform monthly pregnancy tests up to 30 days after last dose of the study drug and agree to use reliable contraception from screening up to 1 month following discontinuation of the study treatment. Birth control is not required in male study participants.²

Cumulatively, since International Birth Date (21 December 2015) and up to 20 December 2023, 96 confirmed pregnancies in UPTRAVI-treated patients have been reported, including 20 from interventional clinical trials, 44 from noninterventional solicited clinical studies, and 32 from a spontaneous source (6 spontaneous cases were from literature source).³

Drug exposure was reported in the first trimester in 43 cases (including 2 cases also reporting exposure during the second trimester and 2 cases reporting exposure throughout the pregnancy), second and third trimesters in 1 case, only second trimester in 1 case, only third trimester in 1 case, and time of exposure was unknown in 47 cases. In 2 cases, exposure was reported before conception.³

Thirty-three pregnant patients gave birth, of whom 4 cases reported live birth of a term baby, 17 cases reported live births with no gestational age reported, and the remaining 12 cases reported live births of premature neonates. Nineteen patients gave birth via Caesarean section: 11 babies were premature, born at week 26 (1 case), week 28 (1 case), week 31 (2 cases), week 33 (3 cases), week 34+1 day (1 case), week 35+1 day (3 cases); 3 babies were born at term, born at week 37 (2 cases), week 38 (1 case), and 5 babies for whom gestational age was not reported.³

Of the prematurely born babies, 3 had a congenital anomaly: 1 baby case (born at week 28) reported that the mother was admitted to the hospital as the baby was in distress; a female baby with a birth weight of 815 grams, no Apgar scores provided, and the mother died after birth. Another baby (born at week 31) with neonatal respiratory distress syndrome required positive pressure ventilation due to cyanosis, followed by continuous positive airway pressure, oxygen, and doses of surfactant. An echocardiogram revealed increased pulmonary artery pressure and patent ductus arteriosus (closed after treatment with indomethacin). Another baby (born at week 35+1 day) with respiratory distress syndrome required continuous positive airway pressure and the neonatal echocardiogram showed secundum atrial septal defect; however, the baby was “doing well” at 10 weeks of age. There were no neonatal abnormalities reported for the remaining babies.³

Twenty-three pregnancies had an outcome of abortion (12 induced/elective abortions, 9 spontaneous/missed abortions, 2 unspecified abortions), 9 cases reported an ongoing pregnancy, 1 case was lost to follow up in a patient who died, and 26 cases had an unknown outcome.³

No new safety concern has been identified from the review of data referring to patients who became pregnant while being treated with UPTRAVI. To date, no reports of UPTRAVI use during lactation have been received.³

Information From a Literature Search

Please note that all cases described in the literature are already accounted for in the information provided from the global safety database until the cutoff date (above).

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 15 April 2024.