The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.
There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.
Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).
Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.
Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).
Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.
There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.
Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.
Velpatasvir/Sofosbuvir (Epclusa) is indicated for the treatment of chronic hepatitis C virus genotypes 1-6. No significant effects were found on embryo-fetal growth or pre- and postnatal development in animals with either drug. The molecular weights were about 883 and 529, respectively, whereas plasma protein binding was greater than 99.5% and 61%-65%, respectively. The median terminal half-lives were 15 and 0.5 hours, respectively. Taken in sum, the human embryo-fetal risk with this drug combination appears to be low.
Central nervous system agents
Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.
Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.
Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.
Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.
Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.
Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.
Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.
Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “ Drugs in Pregnancy and Lactation ” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.
Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.
Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.
Muscular disorder agents
Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.
Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.
Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.
Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.
None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.
Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.