Antifungal therapy in pregnancy and lactation Felix Bongomin, M.B., Ch.B., M.Sc.

Intended Learning outcomes To be able to recognise the complexity of treating fungal infections in pregnancy To understand the pharmacokinetic changes of antifungal agents in pregnancy To be aware of the teratogenic and/or embryotoxic effects of antifungals To be aware of the FDA risk categorisation of antifungal agents in pregnancy

General principles The great majority of drugs cross the placenta by “simple diffusion” from high to low concentration Molecular weight of the drug i.e. M.W. <1500 pass ‘placental barrier” by simple diffusion,e.g. All antifungals (Amphotericin B (924.1g/mol), Fluconazole (306.3g/mol) M.W. >1500 doesn’t pass “placental barrier e.g. Heparin. Molecules not bound to protein are available for transfer Molecules highly soluble in fat & in unionized state quickly pass to the fetus Molecules low solubility in fat & in an ionized state slowly pass to the fetus

Physiological changes during pregnancy  in plasma volume  in cardiac output  in renal blood flow and GFR Altered liver enzyme activities ↑ 3A4 & 2C9 activity, ↓2C19 activity  in plasma protein content Delayed gastric emptying William's Obstetrics, 24th edition

Resulting changes in pharmacokinetics ABSORPTION ↓ GI motility causes ↑ drug absorption DISTRIBUTION ↓ Protein binding causes ↑ free drug to be available ↑ in plasma volume causes ↑volume of distribution with ↓plasma concentration METABOLISM ↑ Hepatic metabolism occurs for some drugs EXCRETION ↑ Renal blood flow & GFR causes some drugs to clear the body faster.

The effect of a drug on the growing fetus Depends on:- 1. The dose absorbed by the mother 2. The period of gestation 3. Exposure time (duration of therapy) 4. Degradation products (metabolites)

The periods of gestation Pre-implantation – 2 weeks post conception No teratogenicity (low dose) Spontaneous abortions After implantation 3-8 weeks (embryogenic period) Teratogenicity (congenital foetal malformations) 9-40 weeks (foetal period) Functional problems rather than gross anatomical anomalies Injury to foetal organs and placenta Learning and/or behavioural abnormalities

1 2 3 4 5 6 7 8 9 16 32 38 Neural tube defects Mental retardation Major congenital anomalies Functional & minor anomalies Embryo Death Highly sensitive period Less sensitive period 1 2 3 4 5 6 7 8 9 16 32 38 TA, ASD, and VSD Amelia/Meromelia Cleft lip CNS TEETH EARS PALATE GENITALIA Early development Main embryonic period (weeks) Fetal period (weeks) EYES Masculinsation Neural tube defects Mental retardation HEART LIMBS UPPER LIP Low-set malformed ears and deafness Microphthalmia, cataracts,glaucoma Enamel hypoplasia Cleft palate Common site(s) of action

Maternal benefit vs. foetal risk assessment Benefits - Foetal loss - Congenital malformations - Organ toxicity - Prematurity - Learning / behavioural abnormalities

How do you prove that a drug is a teratogen? Three criteria must be met: Drug must cause a characteristic set of malformations. Exposure must be during a specific window of vulnerability (3-8 weeks) of gestation. The incidence of malformations should increase with increased dosage and duration of exposure Niebyl, J, Simpson, J, Glob. Libr. Women's Med.,(ISSN: 1756-2228) 2008

FDA Classification of Drugs Risk to Foetus Cat A Controlled studies of women failed to demonstrate a risk to the foetus in the 1st trimester (and there is no evidence of risk in later pregnancy) and the possibility of foetal harm appears remote Cat B Either animal studies have not demonstrated a foetal risk but there are no controlled studies in women, or animal studies have shown an adverse effect but this has not been confirmed in controlled studies in women Cat C Either studies in animal have shown an adverse foetal effect and there are no controlled studies in women or studies in women and animals are not available FDA: Federal Registry. 1980; 44: 37434–7.

FDA Classification of Drugs Risk to Fetus Cat D There is positive evidence of an adverse risk in the human foetus but the benefits from use in pregnant women may outweigh the risk Cat X Studies in animals or humans have demonstrated significant foetal abnormalities and the risk of the use of the drug in pregnant women clearly outweighs any potential benefit FDA: Federal Registry. 1980; 44: 37434–7.

Antifungals in pregnancy: Considerations Antifungal prescription remains a challenge in pregnant women Gross uncertainties regarding foetal toxicity of most antifungals Altered maternal pharmacokinetic parameters Affects efficacy or increase maternal and foetal toxicity Intrinsic activity of a given agent Drug-Drug interactions Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22.

Antifungal drugs and risk category in pregnancy Polyenes Amphotericin B Nystatin* B A FDA category King et al. Clin Infect Dis. 1998; 27:1151 – 60 Pilmis et al. J. Antimicrob Chemother. 2015; 70: 14–22 * Topical only

Antifungal drugs and risk category in pregnancy Azoles FDA category C D Ketoconazole Fluconazole Low-dose regimen (150 mg/day) High-dose regimen (400–600 mg/day) Itraconazole Voriconazole Posaconazole Topical azoles C D C (No human data) C SLIDE TYPE: Template Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22

Antifungal drugs and risk category in pregnancy Echinocandins #No human data Caspofungin Micafungin Anidulafungin C# FDA category # no human data Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22

Antifungal drugs and risk category in pregnancy Other antifungals Flucytosine Terbinafine Griseofulvin Cotrimoxazole C B D FDA category Pilmis. et al J Antimicrob Chemother. 2015; 70: 14–22

Teratogenic profile of antifungals Ketoconazole: Affects sex organ differentiation in the foetus (Animal studies) Fluconazole: Craniofacial and rib abnormalities, and congenital heart diseases (Rodents & rabbits studies, case reports in humans). Low dose is safe Itraconazole: Craniofacial and rib abnormalities (No evidence in clinical studies esp. in first trimester) Voriconazole: Skeletal and visceral abnormalities (No evidence in clinical studies ) Posaconazole: Skeletal malformations and rib abnormalities (No published human data) Sonino et al. N Eng J Med. 1987; 317: 812-8 Tiboni et al. Res Commun Chem Pathol Pharmacol. 1993; 79: 381–4. Mølgaard-Nielsen et al. N Engl J Med. 2013;369:830-9

Teratogenic profile of antifungals Ossification and rib malformations Animal studies Caspofungin Visceral abnormalities and abortions Animal studies Micafungin Skeletal abnormalities Animal studies Anidulafungin Cancidas Package Insert. 2001. Cappelletty et al Pharmacotherapy 2007; 27: 369–88. Eraxis Package Insert. 2006.

Teratogenic profile of antifungals Flucytosine Bone and craniofacial malformations (reported from aborted foetuses) Only in first trimester, no evidence of adverse outcomes in second and third trimester (limited case reports) Amphotericin B No teratogenicity in rodents or rabbits even in first trimester. Case reports in humans (No foetal abnormalities) Cotrimoxazole Neural tube defects (spina bifida), congenital heart diseases, cleft lips and palates, club foot Pilmis. et al J Antimicrob Chemother. 2015; 70: 14–22

Conclusion Amphotericin B and its lipid derivatives are considered the cornerstone of treatment in any invasive fungal infection during pregnancy Fluconazole could be considered after the first trimester in the absence of an alternative agent. Effective contraception should be continued throughout treatment and for 2 months thereafter during itraconazole therapy Voriconazole is contraindicated in pregnancy Embryo-fetotoxic in rabbits, lack of human data Superficial infections during pregnancy require topical treatment, which can be prescribed throughout pregnancy, including topical azoles. Superficial fungal infections requiring systemic treatment, like dermatophytic onychomycosis, chromomycosis and mycetoma, should be treated after delivery.