A review of 2015 drug approvals: Safety in pregnancy and lactation

The Food and Drug Administration approved 45 new drugs in 2015. Currently, lesinurad (Zurampic) to treat high blood uric levels associated with gout, is not yet available. Another agent, aripiprazole (Aristada) for the treatment of schizophrenia, was initially approved in 2004 and is included in “Drugs in Pregnancy and Lactation,” 10th ed. (Philadelphia: Walters Kluwer: 2014, pp. 83-5).

There are three new multidrug combinations. Ceftazidime-avibactam (Avycaz) is indicated for complicated intra-abdominal and urinary tract infections, including pyelonephritis, when there are limited or no alternative treatment options. Lumacaftor-ivacaftor (Orkambi) is used to treat cystic fibrosis. There are no human pregnancy data for these two combination products but, based on animal data, they can be classified as low risk (no developmental toxicity in two or more animal species). There also is a four-drug combination that is a complete regimen for the treatment of HIV-1 infections: elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya). There is one reference citing the use of this combination drug in human pregnancy. It resulted in a healthy full-term infant. Because of its indication, this drug product should not be withheld because of pregnancy.

Asfotase (Strensiq) is a tissue nonspecific alkaline phosphatase. It is indicated for the treatment of perinatal/infantile and juvenile-onset hypophosphatasia. The animal data suggest low risk but it is doubtful that this drug will be used in pregnancy. In studies conducted by the manufacturer, the oldest patient age was 12.6 years.

Dinutuximab (Unituxin) is indicated for the treatment of neuroblastoma, an extracranial solid cancer that occurs in children. There are no studies in pregnant animals or humans.

The remaining 38 agents can be classified into the following categories: anticoagulant (2), antidiarrheal (1), antidiabetic (1), antidote (3), antiemetic (1), antifungal (1), antilipemic (2), antineoplastic (13), antipsychotic (2), antiviral (1), bile acid (2), cardiovascular (2), female sexual dysfunction (1), immunomodulator (1), lysosomal acid lipase deficiency (1), parathyroid hormone (1), pyrimidine analog (1), and respiratory (2).

Only two (cholic acid and ivabradine) of these 38 drugs have any human pregnancy data. Thus, the embryo-fetal risk has to be estimated using only animal data. However, an analysis of 1,154 drugs found that animal data raised the possibility of human developmental toxicity in 311 drugs, which was eventually confirmed in 75 drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5). Nevertheless, in some cases the maternal benefit will outweigh the risk based on animal data.

Anticoagulants

The two anticoagulants are cangrelor (Kengreal), indicated as an adjunct to percutaneous coronary intervention to reduce the risk of myocardial infarction, and edoxaban (Savaysa), to reduce the risk of stroke and embolism in patients with atrial fibrillation and for the treatment of deep vein thrombosis and pulmonary embolism. Although the animal data for cangrelor suggest moderate risk (developmental toxicity in one animal species), the potential benefit to the mother outweighs the risk. The animal data for edoxaban suggest low risk.

Antidiarrheal

Eluxadoline (Viberzi) is indicated for the treatment of irritable bowel syndrome with diarrhea. The animal data suggest low risk.

Antidiabetic

The animal data also suggest low risk for insulin degludec (Tresiba), a long-acting human insulin analog.

Antidote

Sugammadex (Bridion), an antidote, is indicated for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery. The animal data suggest risk (developmental toxicity in two or more animal species). Another antidote, idarucizumab (Praxbind) is a humanized monoclonal antibody fragment. It is indicated to reverse the anticoagulant effects of dabigatran. Animal reproduction studies have not been conducted. If indicated, the drug should not be withheld because of pregnancy. The third antidote is patiromer (Veltassa). It is a potassium binder used for the treatment of hyperkalemia. It should not be used for life-threatening hyperkalemia because of its delayed onset of action. It is not absorbed systemically. Because it can bind other drugs in the gut, other oral medications should be given at least 6 hours before or after patiromer.

Antiemetic

©moodboard/Thinkstock

The antiemetic drug rolapitant (Varubi) is used, in combination with other antiemetics, for patients receiving antineoplastics. Animal data suggest moderate risk.

Antifungal

The triazole antifungal, isavuconazonium (Cresemba) is used for the treatment of invasive aspergillosis or invasive mucormycosis. Low doses of the drug caused perinatal death and skeletal defects in rats, similar to other azole antifungal agents.

Antilipemic agents

There are two antilipemic agents; alirocumab (Praluent) and evolocumab (Repatha). Alirocumab, a monoclonal antibody, is combined with statin therapy. Statins are contraindicated in pregnancy because interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia and there is potential for embryo-fetal risk. Thus, alirocumab is also contraindicated during pregnancy. The same reasoning applies to evolocumab, an immunoglobulin, that is also given with statins.

Antineoplastic

There are 13 new antineoplastic agents that are often combined with other agents. They all can be classified as contraindicated in pregnancy, but the maternal benefit has to be weighed against the potential for embryo-fetal harm. Moreover, they are usually indicated when older drugs and treatments have not been effective. If the drug must be used in pregnancy, avoiding the first trimester should be a priority.

Sonidegib (Odomzo) is used for the treatment of basal cell carcinoma. The new agent for breast cancer is palbociclib (Ibrance). It is combined with letrozole, an antineoplastic that has caused spontaneous abortions and birth defects. A combination drug indicated for metastatic colorectal cancer is trifluridine/tipiracil (Lonsurf).

There are three new drugs that are indicated for non–small-cell lung cancer: alectinib (Alecensa), necitumumab (Portrazza), and osimertinib (Tagrisso). Alectinib and osimertinib are kinase inhibitors, whereas necitumumab is a epidermal growth factor receptor antagonist. The latter agent is a first-line drug that is combined with gemcitabine and cisplatin, both of which can cause birth defects.

The drug used for metastatic liposarcoma or leiomyosarcoma is trabectedin (Yondelis), an alkylating drug. There are no animal data, but the drug’s mechanism of action suggests that it can cause fetal harm. Cobimetinib (Cotellic), a kinase inhibitor, is indicated for the treatment of metastatic melanoma in combination with vemurafenib, another kinase inhibitor. The animal data and mechanism of action suggest that the drug could cause fetal harm.

There are four new agents for the treatment of multiple myeloma: panobinostat (Farydak), daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro). Panobinostat, a histone deacetylase inhibitor, is combined with bortezomib (a proteasome inhibitor) and dexamethasone. The animal data suggest risk. The manufacturer recommends effective contraception while taking the drug and for at least 1 month after the last dose. Daratumumab is a monoclonal antibody. There are no animal data, but based on its mechanism of action, the drug may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. The immunostimulatory antibody elotuzumab is given in combination with lenalidomide, an analog of thalidomide, and dexamethasone. There are no pregnancy data in animals or humans with lenalidomide, but this agent is contraindicated in pregnancy because of its relationship to thalidomide. Ixazomib, a proteasome inhibitor, is also given in combination with lenalidomide and dexamethasone, so the concerns are the same.

A new drug for thyroid cancer is lenvatinib (Lenvima), a tyrosine kinase inhibitor. The animal data suggest risk.

Antipsychotics

The two atypical antipsychotics are brexpiprazole (Rexulti) and cariprazine (Vraylar). Both drugs are included in National Pregnancy Registry for Atypical Antipsychotics. Information concerning the registry can be obtained by calling 1-866-961-2388 or at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Brexpiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. The animal data suggest low risk. Cariprazine is indicated for the treatment of schizophrenia and for the treatment of manic or mixed episodes associated with bipolar I disorder. The animal data suggest moderate risk.

Antiviral

Daclatasvir (Daklinza) is an antiviral agent indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic hepatitis C virus genotype 1 or 3 infection. The animal data suggest low risk but, if ribavirin is used, the combination is contraindicated.

Bile acid

There are two new bile acid products. Cholic acid (Cholbam), is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects and for peroxisomal disorders, including Zellweger spectrum disorders. Although studies in pregnant women or animals have not been conducted, the manufacturer is aware of some case reports that resulted in healthy infants.

Deoxycholic acid (Kybella) is a cytolytic agent that is indicated for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat in adults. The drug caused no fetal harm in rats but did in rabbits, which may have been due to maternal toxicity.

Cardiovascular agents

There are two new cardiovascular agents. Ivabradine (Corlanor) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that is indicated to reduce the risk of hospitalization for worsening heart failure. The animal data suggest risk. A 2001 case report described the use of the drug in a pregnant woman. She suffered a cardiopulmonary arrest in her 10th week of pregnancy and was successfully treated with several drugs, including ivabradine. Ivabradine was stopped 1 month later. She gave birth at term to a normal healthy male infant.

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. The combination is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. There is ample evidence that exposure to valsartan in the second half of pregnancy can cause severe fetal/neonatal toxicity including death.

Sexual dysfunction

Flibanserin (Addyi) is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. The animal data suggest moderate risk. The simultaneous use of alcohol increases the risk of severe hypotension and syncope. The drug is available only through a restricted program called the Addyi REMS Program.

Immunomodulator

The new immunomodulator is secukinumab (Cosentyx). It is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy of phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis. The animal data suggest low risk.

Lysosomal acid lipase deficiency treatment

Sebelipase (Kanuma) is a lysosomal cholesteryl ester and triacylglycerol-specific enzyme that is indicated for the treatment of lysosomal acid lipase deficiency. The animal data suggest low risk.

Parathyroid hormone

Parathyroid hormone (Natpara) is used as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathryoidism. The animal data in one species suggest moderate risk. Moreover, because of the risk of osteosarcoma, the drug should be used only in patients who cannot be well controlled on calcium and active forms of vitamin D alone.

Pyrimidine analog

Uridine (Xuriden) is a pyrimidine analog for uridine replacement. It is indicated for the treatment of hereditary orotic aciduria. The animal data suggest low risk.

Respiratory agents

The two respiratory agents are mepolizumab (Nucala) and selexipag (Uptravi). Mepolizumab is an interleukin-5 monoclonal antibody. It is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype. The animal data suggest low risk. Selexipag is a prostacyclin receptor agonist that is used for the treatment of pulmonary arterial hypertension to delay disease progression and reduce the risk of hospitalization. The animal data suggest low risk.

Lactation

Use of the above drugs during human lactation has not been reported. It is likely that many of these agents will be excreted into breast milk. If a new agent is being taken by a woman who is or will be breastfeeding, the drug’s product information should be checked for the most common adverse reactions noted in nonpregnant patients and the nursing infant should be monitored for these effects.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

The Food and Drug Administration approved 45 new drugs in 2015. Currently, lesinurad (Zurampic) to treat high blood uric levels associated with gout, is not yet available. Another agent, aripiprazole (Aristada) for the treatment of schizophrenia, was initially approved in 2004 and is included in “Drugs in Pregnancy and Lactation,” 10th ed. (Philadelphia: Walters Kluwer: 2014, pp. 83-5).

There are three new multidrug combinations. Ceftazidime-avibactam (Avycaz) is indicated for complicated intra-abdominal and urinary tract infections, including pyelonephritis, when there are limited or no alternative treatment options. Lumacaftor-ivacaftor (Orkambi) is used to treat cystic fibrosis. There are no human pregnancy data for these two combination products but, based on animal data, they can be classified as low risk (no developmental toxicity in two or more animal species). There also is a four-drug combination that is a complete regimen for the treatment of HIV-1 infections: elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya). There is one reference citing the use of this combination drug in human pregnancy. It resulted in a healthy full-term infant. Because of its indication, this drug product should not be withheld because of pregnancy.

Asfotase (Strensiq) is a tissue nonspecific alkaline phosphatase. It is indicated for the treatment of perinatal/infantile and juvenile-onset hypophosphatasia. The animal data suggest low risk but it is doubtful that this drug will be used in pregnancy. In studies conducted by the manufacturer, the oldest patient age was 12.6 years.

Dinutuximab (Unituxin) is indicated for the treatment of neuroblastoma, an extracranial solid cancer that occurs in children. There are no studies in pregnant animals or humans.

The remaining 38 agents can be classified into the following categories: anticoagulant (2), antidiarrheal (1), antidiabetic (1), antidote (3), antiemetic (1), antifungal (1), antilipemic (2), antineoplastic (13), antipsychotic (2), antiviral (1), bile acid (2), cardiovascular (2), female sexual dysfunction (1), immunomodulator (1), lysosomal acid lipase deficiency (1), parathyroid hormone (1), pyrimidine analog (1), and respiratory (2).

Only two (cholic acid and ivabradine) of these 38 drugs have any human pregnancy data. Thus, the embryo-fetal risk has to be estimated using only animal data. However, an analysis of 1,154 drugs found that animal data raised the possibility of human developmental toxicity in 311 drugs, which was eventually confirmed in 75 drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5). Nevertheless, in some cases the maternal benefit will outweigh the risk based on animal data.

Anticoagulants

The two anticoagulants are cangrelor (Kengreal), indicated as an adjunct to percutaneous coronary intervention to reduce the risk of myocardial infarction, and edoxaban (Savaysa), to reduce the risk of stroke and embolism in patients with atrial fibrillation and for the treatment of deep vein thrombosis and pulmonary embolism. Although the animal data for cangrelor suggest moderate risk (developmental toxicity in one animal species), the potential benefit to the mother outweighs the risk. The animal data for edoxaban suggest low risk.

Antidiarrheal

Eluxadoline (Viberzi) is indicated for the treatment of irritable bowel syndrome with diarrhea. The animal data suggest low risk.

Antidiabetic

The animal data also suggest low risk for insulin degludec (Tresiba), a long-acting human insulin analog.

Antidote

Sugammadex (Bridion), an antidote, is indicated for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery. The animal data suggest risk (developmental toxicity in two or more animal species). Another antidote, idarucizumab (Praxbind) is a humanized monoclonal antibody fragment. It is indicated to reverse the anticoagulant effects of dabigatran. Animal reproduction studies have not been conducted. If indicated, the drug should not be withheld because of pregnancy. The third antidote is patiromer (Veltassa). It is a potassium binder used for the treatment of hyperkalemia. It should not be used for life-threatening hyperkalemia because of its delayed onset of action. It is not absorbed systemically. Because it can bind other drugs in the gut, other oral medications should be given at least 6 hours before or after patiromer.

Antiemetic

©moodboard/Thinkstock

The antiemetic drug rolapitant (Varubi) is used, in combination with other antiemetics, for patients receiving antineoplastics. Animal data suggest moderate risk.

Antifungal

The triazole antifungal, isavuconazonium (Cresemba) is used for the treatment of invasive aspergillosis or invasive mucormycosis. Low doses of the drug caused perinatal death and skeletal defects in rats, similar to other azole antifungal agents.

Antilipemic agents

There are two antilipemic agents; alirocumab (Praluent) and evolocumab (Repatha). Alirocumab, a monoclonal antibody, is combined with statin therapy. Statins are contraindicated in pregnancy because interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia and there is potential for embryo-fetal risk. Thus, alirocumab is also contraindicated during pregnancy. The same reasoning applies to evolocumab, an immunoglobulin, that is also given with statins.

Antineoplastic

There are 13 new antineoplastic agents that are often combined with other agents. They all can be classified as contraindicated in pregnancy, but the maternal benefit has to be weighed against the potential for embryo-fetal harm. Moreover, they are usually indicated when older drugs and treatments have not been effective. If the drug must be used in pregnancy, avoiding the first trimester should be a priority.

Sonidegib (Odomzo) is used for the treatment of basal cell carcinoma. The new agent for breast cancer is palbociclib (Ibrance). It is combined with letrozole, an antineoplastic that has caused spontaneous abortions and birth defects. A combination drug indicated for metastatic colorectal cancer is trifluridine/tipiracil (Lonsurf).

There are three new drugs that are indicated for non–small-cell lung cancer: alectinib (Alecensa), necitumumab (Portrazza), and osimertinib (Tagrisso). Alectinib and osimertinib are kinase inhibitors, whereas necitumumab is a epidermal growth factor receptor antagonist. The latter agent is a first-line drug that is combined with gemcitabine and cisplatin, both of which can cause birth defects.

The drug used for metastatic liposarcoma or leiomyosarcoma is trabectedin (Yondelis), an alkylating drug. There are no animal data, but the drug’s mechanism of action suggests that it can cause fetal harm. Cobimetinib (Cotellic), a kinase inhibitor, is indicated for the treatment of metastatic melanoma in combination with vemurafenib, another kinase inhibitor. The animal data and mechanism of action suggest that the drug could cause fetal harm.

There are four new agents for the treatment of multiple myeloma: panobinostat (Farydak), daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro). Panobinostat, a histone deacetylase inhibitor, is combined with bortezomib (a proteasome inhibitor) and dexamethasone. The animal data suggest risk. The manufacturer recommends effective contraception while taking the drug and for at least 1 month after the last dose. Daratumumab is a monoclonal antibody. There are no animal data, but based on its mechanism of action, the drug may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. The immunostimulatory antibody elotuzumab is given in combination with lenalidomide, an analog of thalidomide, and dexamethasone. There are no pregnancy data in animals or humans with lenalidomide, but this agent is contraindicated in pregnancy because of its relationship to thalidomide. Ixazomib, a proteasome inhibitor, is also given in combination with lenalidomide and dexamethasone, so the concerns are the same.

A new drug for thyroid cancer is lenvatinib (Lenvima), a tyrosine kinase inhibitor. The animal data suggest risk.

Antipsychotics

The two atypical antipsychotics are brexpiprazole (Rexulti) and cariprazine (Vraylar). Both drugs are included in National Pregnancy Registry for Atypical Antipsychotics. Information concerning the registry can be obtained by calling 1-866-961-2388 or at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Brexpiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. The animal data suggest low risk. Cariprazine is indicated for the treatment of schizophrenia and for the treatment of manic or mixed episodes associated with bipolar I disorder. The animal data suggest moderate risk.

Antiviral

Daclatasvir (Daklinza) is an antiviral agent indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic hepatitis C virus genotype 1 or 3 infection. The animal data suggest low risk but, if ribavirin is used, the combination is contraindicated.

Bile acid

There are two new bile acid products. Cholic acid (Cholbam), is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects and for peroxisomal disorders, including Zellweger spectrum disorders. Although studies in pregnant women or animals have not been conducted, the manufacturer is aware of some case reports that resulted in healthy infants.

Deoxycholic acid (Kybella) is a cytolytic agent that is indicated for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat in adults. The drug caused no fetal harm in rats but did in rabbits, which may have been due to maternal toxicity.

Cardiovascular agents

There are two new cardiovascular agents. Ivabradine (Corlanor) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that is indicated to reduce the risk of hospitalization for worsening heart failure. The animal data suggest risk. A 2001 case report described the use of the drug in a pregnant woman. She suffered a cardiopulmonary arrest in her 10th week of pregnancy and was successfully treated with several drugs, including ivabradine. Ivabradine was stopped 1 month later. She gave birth at term to a normal healthy male infant.

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. The combination is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. There is ample evidence that exposure to valsartan in the second half of pregnancy can cause severe fetal/neonatal toxicity including death.

Sexual dysfunction

Flibanserin (Addyi) is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. The animal data suggest moderate risk. The simultaneous use of alcohol increases the risk of severe hypotension and syncope. The drug is available only through a restricted program called the Addyi REMS Program.

Immunomodulator

The new immunomodulator is secukinumab (Cosentyx). It is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy of phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis. The animal data suggest low risk.

Lysosomal acid lipase deficiency treatment

Sebelipase (Kanuma) is a lysosomal cholesteryl ester and triacylglycerol-specific enzyme that is indicated for the treatment of lysosomal acid lipase deficiency. The animal data suggest low risk.

Parathyroid hormone

Parathyroid hormone (Natpara) is used as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathryoidism. The animal data in one species suggest moderate risk. Moreover, because of the risk of osteosarcoma, the drug should be used only in patients who cannot be well controlled on calcium and active forms of vitamin D alone.

Pyrimidine analog

Uridine (Xuriden) is a pyrimidine analog for uridine replacement. It is indicated for the treatment of hereditary orotic aciduria. The animal data suggest low risk.

Respiratory agents

The two respiratory agents are mepolizumab (Nucala) and selexipag (Uptravi). Mepolizumab is an interleukin-5 monoclonal antibody. It is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype. The animal data suggest low risk. Selexipag is a prostacyclin receptor agonist that is used for the treatment of pulmonary arterial hypertension to delay disease progression and reduce the risk of hospitalization. The animal data suggest low risk.

Lactation

Use of the above drugs during human lactation has not been reported. It is likely that many of these agents will be excreted into breast milk. If a new agent is being taken by a woman who is or will be breastfeeding, the drug’s product information should be checked for the most common adverse reactions noted in nonpregnant patients and the nursing infant should be monitored for these effects.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

The Food and Drug Administration approved 45 new drugs in 2015. Currently, lesinurad (Zurampic) to treat high blood uric levels associated with gout, is not yet available. Another agent, aripiprazole (Aristada) for the treatment of schizophrenia, was initially approved in 2004 and is included in “Drugs in Pregnancy and Lactation,” 10th ed. (Philadelphia: Walters Kluwer: 2014, pp. 83-5).

There are three new multidrug combinations. Ceftazidime-avibactam (Avycaz) is indicated for complicated intra-abdominal and urinary tract infections, including pyelonephritis, when there are limited or no alternative treatment options. Lumacaftor-ivacaftor (Orkambi) is used to treat cystic fibrosis. There are no human pregnancy data for these two combination products but, based on animal data, they can be classified as low risk (no developmental toxicity in two or more animal species). There also is a four-drug combination that is a complete regimen for the treatment of HIV-1 infections: elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya). There is one reference citing the use of this combination drug in human pregnancy. It resulted in a healthy full-term infant. Because of its indication, this drug product should not be withheld because of pregnancy.

Asfotase (Strensiq) is a tissue nonspecific alkaline phosphatase. It is indicated for the treatment of perinatal/infantile and juvenile-onset hypophosphatasia. The animal data suggest low risk but it is doubtful that this drug will be used in pregnancy. In studies conducted by the manufacturer, the oldest patient age was 12.6 years.

Dinutuximab (Unituxin) is indicated for the treatment of neuroblastoma, an extracranial solid cancer that occurs in children. There are no studies in pregnant animals or humans.

The remaining 38 agents can be classified into the following categories: anticoagulant (2), antidiarrheal (1), antidiabetic (1), antidote (3), antiemetic (1), antifungal (1), antilipemic (2), antineoplastic (13), antipsychotic (2), antiviral (1), bile acid (2), cardiovascular (2), female sexual dysfunction (1), immunomodulator (1), lysosomal acid lipase deficiency (1), parathyroid hormone (1), pyrimidine analog (1), and respiratory (2).

Only two (cholic acid and ivabradine) of these 38 drugs have any human pregnancy data. Thus, the embryo-fetal risk has to be estimated using only animal data. However, an analysis of 1,154 drugs found that animal data raised the possibility of human developmental toxicity in 311 drugs, which was eventually confirmed in 75 drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5). Nevertheless, in some cases the maternal benefit will outweigh the risk based on animal data.

Anticoagulants

The two anticoagulants are cangrelor (Kengreal), indicated as an adjunct to percutaneous coronary intervention to reduce the risk of myocardial infarction, and edoxaban (Savaysa), to reduce the risk of stroke and embolism in patients with atrial fibrillation and for the treatment of deep vein thrombosis and pulmonary embolism. Although the animal data for cangrelor suggest moderate risk (developmental toxicity in one animal species), the potential benefit to the mother outweighs the risk. The animal data for edoxaban suggest low risk.

Antidiarrheal

Eluxadoline (Viberzi) is indicated for the treatment of irritable bowel syndrome with diarrhea. The animal data suggest low risk.

Antidiabetic

The animal data also suggest low risk for insulin degludec (Tresiba), a long-acting human insulin analog.

Antidote

Sugammadex (Bridion), an antidote, is indicated for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery. The animal data suggest risk (developmental toxicity in two or more animal species). Another antidote, idarucizumab (Praxbind) is a humanized monoclonal antibody fragment. It is indicated to reverse the anticoagulant effects of dabigatran. Animal reproduction studies have not been conducted. If indicated, the drug should not be withheld because of pregnancy. The third antidote is patiromer (Veltassa). It is a potassium binder used for the treatment of hyperkalemia. It should not be used for life-threatening hyperkalemia because of its delayed onset of action. It is not absorbed systemically. Because it can bind other drugs in the gut, other oral medications should be given at least 6 hours before or after patiromer.

Antiemetic

©moodboard/Thinkstock

The antiemetic drug rolapitant (Varubi) is used, in combination with other antiemetics, for patients receiving antineoplastics. Animal data suggest moderate risk.

Antifungal

The triazole antifungal, isavuconazonium (Cresemba) is used for the treatment of invasive aspergillosis or invasive mucormycosis. Low doses of the drug caused perinatal death and skeletal defects in rats, similar to other azole antifungal agents.

Antilipemic agents

There are two antilipemic agents; alirocumab (Praluent) and evolocumab (Repatha). Alirocumab, a monoclonal antibody, is combined with statin therapy. Statins are contraindicated in pregnancy because interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia and there is potential for embryo-fetal risk. Thus, alirocumab is also contraindicated during pregnancy. The same reasoning applies to evolocumab, an immunoglobulin, that is also given with statins.

Antineoplastic

There are 13 new antineoplastic agents that are often combined with other agents. They all can be classified as contraindicated in pregnancy, but the maternal benefit has to be weighed against the potential for embryo-fetal harm. Moreover, they are usually indicated when older drugs and treatments have not been effective. If the drug must be used in pregnancy, avoiding the first trimester should be a priority.

Sonidegib (Odomzo) is used for the treatment of basal cell carcinoma. The new agent for breast cancer is palbociclib (Ibrance). It is combined with letrozole, an antineoplastic that has caused spontaneous abortions and birth defects. A combination drug indicated for metastatic colorectal cancer is trifluridine/tipiracil (Lonsurf).

There are three new drugs that are indicated for non–small-cell lung cancer: alectinib (Alecensa), necitumumab (Portrazza), and osimertinib (Tagrisso). Alectinib and osimertinib are kinase inhibitors, whereas necitumumab is a epidermal growth factor receptor antagonist. The latter agent is a first-line drug that is combined with gemcitabine and cisplatin, both of which can cause birth defects.

The drug used for metastatic liposarcoma or leiomyosarcoma is trabectedin (Yondelis), an alkylating drug. There are no animal data, but the drug’s mechanism of action suggests that it can cause fetal harm. Cobimetinib (Cotellic), a kinase inhibitor, is indicated for the treatment of metastatic melanoma in combination with vemurafenib, another kinase inhibitor. The animal data and mechanism of action suggest that the drug could cause fetal harm.

There are four new agents for the treatment of multiple myeloma: panobinostat (Farydak), daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro). Panobinostat, a histone deacetylase inhibitor, is combined with bortezomib (a proteasome inhibitor) and dexamethasone. The animal data suggest risk. The manufacturer recommends effective contraception while taking the drug and for at least 1 month after the last dose. Daratumumab is a monoclonal antibody. There are no animal data, but based on its mechanism of action, the drug may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. The immunostimulatory antibody elotuzumab is given in combination with lenalidomide, an analog of thalidomide, and dexamethasone. There are no pregnancy data in animals or humans with lenalidomide, but this agent is contraindicated in pregnancy because of its relationship to thalidomide. Ixazomib, a proteasome inhibitor, is also given in combination with lenalidomide and dexamethasone, so the concerns are the same.

A new drug for thyroid cancer is lenvatinib (Lenvima), a tyrosine kinase inhibitor. The animal data suggest risk.

Antipsychotics

The two atypical antipsychotics are brexpiprazole (Rexulti) and cariprazine (Vraylar). Both drugs are included in National Pregnancy Registry for Atypical Antipsychotics. Information concerning the registry can be obtained by calling 1-866-961-2388 or at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Brexpiprazole is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. The animal data suggest low risk. Cariprazine is indicated for the treatment of schizophrenia and for the treatment of manic or mixed episodes associated with bipolar I disorder. The animal data suggest moderate risk.

Antiviral

Daclatasvir (Daklinza) is an antiviral agent indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic hepatitis C virus genotype 1 or 3 infection. The animal data suggest low risk but, if ribavirin is used, the combination is contraindicated.

Bile acid

There are two new bile acid products. Cholic acid (Cholbam), is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects and for peroxisomal disorders, including Zellweger spectrum disorders. Although studies in pregnant women or animals have not been conducted, the manufacturer is aware of some case reports that resulted in healthy infants.

Deoxycholic acid (Kybella) is a cytolytic agent that is indicated for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat in adults. The drug caused no fetal harm in rats but did in rabbits, which may have been due to maternal toxicity.

Cardiovascular agents

There are two new cardiovascular agents. Ivabradine (Corlanor) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that is indicated to reduce the risk of hospitalization for worsening heart failure. The animal data suggest risk. A 2001 case report described the use of the drug in a pregnant woman. She suffered a cardiopulmonary arrest in her 10th week of pregnancy and was successfully treated with several drugs, including ivabradine. Ivabradine was stopped 1 month later. She gave birth at term to a normal healthy male infant.

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. The combination is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. There is ample evidence that exposure to valsartan in the second half of pregnancy can cause severe fetal/neonatal toxicity including death.

Sexual dysfunction

Flibanserin (Addyi) is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. The animal data suggest moderate risk. The simultaneous use of alcohol increases the risk of severe hypotension and syncope. The drug is available only through a restricted program called the Addyi REMS Program.

Immunomodulator

The new immunomodulator is secukinumab (Cosentyx). It is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy of phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis. The animal data suggest low risk.

Lysosomal acid lipase deficiency treatment

Sebelipase (Kanuma) is a lysosomal cholesteryl ester and triacylglycerol-specific enzyme that is indicated for the treatment of lysosomal acid lipase deficiency. The animal data suggest low risk.

Parathyroid hormone

Parathyroid hormone (Natpara) is used as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathryoidism. The animal data in one species suggest moderate risk. Moreover, because of the risk of osteosarcoma, the drug should be used only in patients who cannot be well controlled on calcium and active forms of vitamin D alone.

Pyrimidine analog

Uridine (Xuriden) is a pyrimidine analog for uridine replacement. It is indicated for the treatment of hereditary orotic aciduria. The animal data suggest low risk.

Respiratory agents

The two respiratory agents are mepolizumab (Nucala) and selexipag (Uptravi). Mepolizumab is an interleukin-5 monoclonal antibody. It is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype. The animal data suggest low risk. Selexipag is a prostacyclin receptor agonist that is used for the treatment of pulmonary arterial hypertension to delay disease progression and reduce the risk of hospitalization. The animal data suggest low risk.

Lactation

Use of the above drugs during human lactation has not been reported. It is likely that many of these agents will be excreted into breast milk. If a new agent is being taken by a woman who is or will be breastfeeding, the drug’s product information should be checked for the most common adverse reactions noted in nonpregnant patients and the nursing infant should be monitored for these effects.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.