ITRACONAZOLE
Drugs in Pregnancy and Lactation.
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Name: ITRACONAZOLE
Class: Antifungal
Risk Factor: CM
Fetal Risk Summary
Itraconazole is a triazole antifungal agent that is structurally related to a number of other antifungal agents, including the imidazole-derivatives butoconazole, clotrimazole, and ketoconazole, and to the triazoles, fluconazole and terconazole (1).
A dose-related increase in toxicity and teratogenicity was found in both rats and mice (2). In pregnant rats treated with a dosage range 5 to 20 times the maximum recommended human dose (MRHD), maternal and embryo toxicity were observed, as were major skeletal malformations. In mice given 10 times the MRHD, maternal toxicity, embryo toxicity, and malformations consisting of encephaloceles or macroglossia occurred.
It is not known if itraconazole crosses the human placenta. The molecular weight (about 706) is low enough that passage to the fetus should be expected.
Cohort data presented at a 1996 meeting on single-dose fluconazole or itraconazole exposures during organogenesis did not demonstrate adverse outcomes in approximately 70 exposed pregnancies (3). However, the FDA has received 14 case reports of malformations following use of itraconazole, 4 of which involved limb defects (includes 1 case of agenesis of the fingers and toes) (3).
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (4). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Itraconazole was taken during the 1st trimester in 41 pregnancies. The outcomes of these pregnancies included 1 ectopic pregnancy, 2 spontaneous abortions, 6 elective abortions, 2 cases lost to follow-up, and 30 normal newborns (1 premature) (4). One of the normal, full-term newborns, however, had a minor congenital anomaly consisting of a thin, prominent and protruding left ear. Although no major congenital malformations were observed, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires.
A prospective cohort study published in 2000 evaluated the pregnancy outcomes of 198 women exposed to itraconazole in the 1st trimester (5). The pregnancy exposures had been reported to the manufacturer, before the outcomes were known, between April 1989 and June 1998. The median itraconazole dose was 200 mg (range 50–800 mg) with a mean therapy duration of 8.5 ± 12.4 days (range 1–90 days). A matched control group (N=198) was formed from pregnant women who had contacted the Motherisk Program, a teratogen information service in Toronto, Canada. The control group had not been exposed to any known teratogens (acceptable exposures were acetaminophen, penicillins, prenatal vitamins, dental radiography, or no exposures). There were no statistical differences between the groups in gravidity, parity, alcohol use, or cigarette smoking, but the maternal age in the study group was less than controls (30.1 vs. 31.0 years, p=0.02). Among pregnancy outcomes, there were no statistical differences between the groups in delivery method, rates of term, preterm, and postterm deliveries, 1- and 5-minute Apgar scores, sex ratios, and rates of neonatal complications. Significantly more pregnancy losses occurred in the exposed group than in controls (p<0.001; relative risk 1.75, 95% confidence interval 1.47–2.09), including spontaneous abortions (12.6% vs. 4.0%), elective abortions (7.5% vs. 0.5%), and fetal deaths (1.5% vs. 1.0%). The authors attributed these differences to group differences, rather than to effects of itraconazole exposure (5). In addition, the birth weight of exposed newborns was lower than controls (3.33 vs. 3.46 kg, p=0.04), but this finding was probably not clinically significant (5). There was no statistical difference between the groups in major congenital malformations. Among the 156 live births in the study group there were five infants (3.2%) with major anomalies (microphthalmia, dysplasia of the right hand, pyloric stenosis, hip joint dysplasia, and congenital heart disease [type not specified]). There were nine newborns (4.8%) with major defects among the 187 controls with live births (congenital heart disease [three cases—two with ventricular septal defect and one not specified], hypospadias requiring surgery [two cases], and one each of oversized tongue, congenital hip dislocation, cleft palate, and Down syndrome with atrioventricular canal). The study had 80% power to detect a 3-fold increased risk of major defects (5), but no evaluation was conducted for minor defects.
In summary, the available human data do not show that itraconazole poses a significant risk for major anomalies in humans. None of the above studies, however, adequately looked for minor malformations. Moreover, another azole antifungal agent, fluconazole, has demonstrated a possible dose-related relationship with major malformations (see Fluconazole). Therefore, the safest course is to avoid itraconazole, if possible, during organogenesis. If inadvertent exposure does occur during the 1st trimester, or if itraconazole must be used during early pregnancy, the woman can be reassured that the risk to her embryo or fetus, if it exists at all, is most likely low.
Breast Feeding Summary
Itraconazole is excreted into human breast milk. Two healthy lactating women each took two oral doses of 200 mg 12 hours apart (total dose 400 mg) (personal communication, EK Cazzaniga and A Chanlam, Janssen Pharmaceuticals, 1996). Neither infant was allowed to nurse during the study. At 4, 24, and 48 hours after the second dose, the average milk concentrations of itraconazole were 70, 28, and 16 ng/mL, respectively. At 72 hours, the milk level was 20 ng/mL in one woman and not detectable (<5 ng/mL) in the other. The average milk:plasma ratios at 4, 24, and 48 hours were 0.51, 1.61, and 1.77, respectively. Using the 4-hour concentration (the approximate time of the peak plasma level), and assuming the infants consumed 500 mL of milk/day, the maximum 24-hour average dose the infants would have received was 35 µg.
Although the above amount seems small, peak plasma concentrations in healthy male volunteers taking itraconazole 200 mg twice daily were not reached until about 15 days (2). The mean peak concentration of the parent compound in these volunteers was 2282 ng/mL, or about 15 times the average peak concentration measured in the two women above. Moreover, the mean plasma concentration of one of the metabolites (hydroxyitraconazole) exceeded that of the parent compound. Additionally, in animal studies, itraconazole accumulated in fatty tissues, omentum, liver, kidney, and skin tissues at levels 2–20 times the corresponding plasma concentration (2). Thus, continuous daily dosing, even with lower doses, should result in milk levels of the drug much higher than those found above and could result in widespread tissue accumulation in nursing infants. Because the potential effects of this exposure have not been studied, women taking itraconazole should probably not breast-feed.
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References
- American Hospital Formulary Service. Drug Information 1997. Bethesda, MD:American Society of Health-System Pharmacists, 1997:93–5.
- Product information. Sporanox. Janssen Pharmaceutica, 2001.
- Rosa F. Azole fungicide pregnancy risks. Presented at the Ninth International Conference of the Organization of Teratology Information Services, May 2–4, 1996, Salt Lake City, Utah.
- Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
- Bar-Oz B, Moretti ME, Bishai R, Mareels G, Van Tittelboom T, Verspeelt J, Koren G. Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol 2000;183:617–20.
Q&A about Itraconazole
He has to take it once every 24 hours, and they are having me give him 21/2 mg each time. The paper I read on-line says to give 10 mg per kg once daily. I don't know if what kg means. It has something to do with weight, I do know he weighs 9 lbs or so. Can someone tell me if that would be correct to give (21/2 mg each 24 hours or not. I don't trust the vet that is filling in for my usual vet. Please help if you know what these measurements mean, relating to his weight. Thanks so much
You did not state what form of medication this is (liquid, capsule). I'm going to assume that it's a liquid, since cats are usually given liquids. Usually, liquids have so many milligrams (mg) per milliliter (mL). So, 2 1/2 cc or mL does not necessarily equal 2 1/2 milligrams.
For example, if a medication is 5mg/mL and you gave 2cc or 2mL, you'd actually be giving 10mg.
A kg is a kilogram, which is the metric form of weight measurement. A kg is equal to approximately 2.2 pounds.
*1cc is the same as 1mL
i'm taking the itraconazole pills for that toenail fungus. how many months do you usually have to take the pills for?
How much does it cost if I take them to the vet? And how much without going to the vet (perhaps some remedies are over-the-counter or off-the-shelf?).
How much for:
1.5mg ivermectin
30mg Advantage
liquid griseofulvin (150mg active ingredient?)
tablet griseofulvin (150mg active ingredient?)
povidone-iodine shampoo
elimite cream
lindane shampoo
selenium sulphide shampoo
itraconazole shampoo
ketoconazole shampoo (e.g. Nizoral)
Revolution (selamectin)
Which of the above list needs a prescription (and by vet or human physician)? What country is your pricing valid for? Where & how can I get the drug(s)/product(s)?
My last period was mid. Feb and until today it hasn't come yet. I went to see the doctor on April 1 and tested -ve. The doctor checked & said that I have yeast & bacteria infection. So she prescribed sporal Itraconazol & Flagyl and gave me Primolut-N. So far I have been taking both sporal & Flagyl only. I'm scared to take Primolut-N. The side effect from the med is dark almost brown urine. Today is my 4th day taking the med. Yday my saliva tasted different and today. Some friends say I am pregnant & should stop the med. What is your opinion? Please help. I really need to know for the baby's safty. Thanks.
FLAGYL
* Crosses human placenta.
* Use in 1st trimester is controversial, possible association with congenital defects (Mental retardation, dislocated hip, hydrocele, cleft lip and palate, holotelencephaly, optic atrophy, hand defects, metatarsus varus).
* Contraindicated in 1st trimester, acceptable in 2nd and 3rd trimesters if alternatives failed.
Primolut- N
* Suggested association between the use of progestational agents including norethindrone and increased risk of malformations including cardiovascular defects and hypospadias.
* Suggested possible association between first trimester exposure to norethindrone and spina bifida and hydrocephalus.
* Norethindrone causes musculinization of the female fetus if used any time durig pregnancy.
Sporal Itraconazole
No adequate human data but suggested association with limb defects when used in pregnancy.
For more information visit my free website
http://www.pregnancy-guidelines.com
http://birthdefectcauses.blogspot.com
what can i do to improve the liver the medician is hard on the liver itraconazole.
"Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition 15 of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels."
I don't know what that means. It's something I looked up for my birth control pill "Loestrin 24 Fe". I'm trying to find out if absorbic acid (vitamin C) will decrease the effect of the pill or not.
I have been diagnosed with aspergillosis, back in december last year,thay took my right lung, I have not been well since, I have hadamphotericin b i.v., and i am still taking itraconazole, my elbows fell like they will fall off anytime now, passing out alot, coughing up blood, sweating all the time, it seems the drugs do no good, does anyone know of people with this condition?
is it safe to still take my itraconazole for my nail infection,thanks you for your time,
Go to :http://emc.medicines.org.uk/
Enter eMC and type malarone in to the quick search.
