A Latin sentence says: anceps remedium melius quam nullum – an uncertain medicine is better than none. Have you ever wondered why the use of drugs in some populations of patients (such as pregnant women or children) is especially encouraged to be reported? The answer to this question is straightforward – it is impossible to carry out a clinical trial in every population of patients. Due to this, we do not have enough data to introduce indications in the product information for these groups of patients. But still, we need to bear in mind that those patients need and deserve effective and safe pharmacotherapy. At this point, physicians need to analyze the benefit-risk balance of a particular drug product and tailor the therapy according to their knowledge and experience. Sometimes, they have to use the medicinal product out of the scope of the approved indications to improve their patient’s health.
Off-label use of medicinal products
According to the European Medicines Agency, off-label use is the “use of a medicine for an unapproved indication or in an unapproved age group, dosage, or route of administration” [1]. Such treatment is not forbidden by law, but it is the physician’s responsibility to gain extended knowledge regarding the considered medicine, the patient’s age and condition and what is crucial – to gain their consent to be treated beyond the approved indications [2].
The origin of the product labelling dates back to 1906 when the Pure Food and Drugs Act of 1906 in the United States of America was adopted. The Act said that for some drugs, ingredient information should be placed on the label. Since then, the legislation has developed into regulations that are applicable nowadays [3]. Despite extensive knowledge gained during clinical trials, there is still a multitude of undiscovered or unproven evidence-based medical properties of the active substances. Physicians can derive knowledge from medical literature describing case reports of patients treated outside the approved indications or posology. Surprisingly, off-label use can become a widely accepted practice and even a standard treatment [4].
Newborns are a particular group of patients in which prematurity and low birth weight significantly affect the pharmacokinetics and pharmacodynamics of drugs. If hospitalized, this population may need antibiotics for systemic use of drugs acting on the nervous or respiratory system, as well as cardiovascular drugs. A worldwide practice shows that the prescription of off-label medicines in this group equals about half of the medications (37% to 55%). Therefore, there must be stress on the development of studies which shall broaden the knowledge of drug use in children. Hopefully, several international organizations, such as the Pediatric Pharmacology Research Units (PPRU) Network, were created to perform drug-labeling clinical trials in children [5,6].
Medicines usage during pregnancy
Pregnancy and breastfeeding are unique stages in a woman’s life where the safety and effectiveness of medications play a critical role in the well-being of both the mother and the unborn or nursing child. While it is essential to rely on approved medications for these populations, there are instances where off-label drug use may be necessary. In this article, we will delve into the use of off-label drugs in pregnant and breastfeeding women, exploring the considerations for safety and the importance of ensuring treatment options in pharmacotherapy. Pregnant women represent a vulnerable group of patients who need special attention during treatment. Unfortunately, there are also significant gaps in knowledge regarding the safety, dosage and long-term effects of the drugs used in this population. Physiological changes that occur in pregnant women significantly change the pharmacokinetics of the drugs. Moreover, during pregnancy, the course and symptoms of the condition can be modified [7]. There is no legal or regulatory requirement for new drugs to be tested on pregnant women. In pregnant women, the limited data on drug safety during pregnancy often leads to off-label drug use. This leads to over 80% of pregnant patients routinely being treated with drugs which have not been adequately studied in pregnancy [8].
But why are in-depth studies in this particular group so crucial? Some of us may remember the tragic outcome caused by the administration of thalidomide in pregnant women widespread in Europe, Australia and Japan in the 1950s. The drug was used in the treatment of nausea – a common symptom during pregnancy. It was considered as safe and effective. Its toxicity was studied on rats only and did not reveal a potential threat to foetuses. Administration in a vast population of pregnant women resulted in over 10,000 cases of phocomelia – a malformation leading to limb formation anomalies. This tragedy led to the creation of detailed testing protocols and detailed toxicity testing of the developed drug products [9].
It is crucial for healthcare providers to carefully evaluate the available evidence and make informed decisions when prescribing off-label drugs to pregnant women. Close monitoring and communication between healthcare providers and patients are essential to ensure the safety of both the mother and the developing fetus.
To ensure increased knowledge about the safety of using drugs during pregnancy for both mothers and future children, it is crucial to report each use of the drug during pregnancy, as we write below.
Pregnancy Outcome Reporting Form – reporting use of medicinal products in pregnant woman
A valuable contribution to the knowledge on this topic may provide a post-authorization register of pregnancy exposure. Unlike other patient groups, pharmaceutical companies are legally obliged to register each case of reported use (not only the adverse event but the medicinal product intake itself) of the drug in pregnant woman on a Pregnancy Outcome Reporting Form (PORF). Data enclosed in this form enables to gather information regarding the use of the drug during pregnancy and the impact it had on a developing foetus [7]. Therefore, it is essential to collect data regarding drug products’ intake during pregnancy and follow up on the course of childbirth and even on the future development of the child.
Breastfeeding and medicines – the safety during lactation
Similarly, breastfeeding women face challenges when it comes to medication use, as many drugs can pass into breast milk and potentially impact the nursing infant. Human milk is a complete food for newborns, and its consumption plays a significant role in their development. It is a complex emulsion consisting not only of highly desired nutrient substances but also other compounds which may harm this little developing human being. Breast milk may contain drugs, pesticides, carcinogens and environmental pollutants [10]. Hopefully, the amount of drug excreted in milk over the feeding period is relatively small because the mammary gland is not a major drug-eliminating organ. This way, only a tiny fraction of the dose administered to breastfeeding women is secreted to milk. But still, there are reports of toxicity in infants breastfed by women receiving medications [11].
The possible secretion of drugs into breast milk makes mothers face a dilemma of whether to start the therapy or continue breastfeeding. In cases where there is insufficient data on the safety of medication during breastfeeding, healthcare providers may need to consider off-label drug use. Such situations should always be deeply analyzed and discussed with healthcare professionals to balance the benefits and harms. Internet resources are here to help as well. A web tool supported by a group of Spanish paediatricians – https://www.e-lactancia.org/ provides verified information on the compatibility of products, including drugs with breastfeeding [12]. When you are a breastfeeding mom and wonder which drug products will be safe for use during lactation, you can always check on this website. However, what needs to be kept in mind is that all products, especially those for this special period of life, should be administered after consultation with a healthcare professional.
We must all remember and understand that each person can become sick and should have access to medicinal products to improve their well-being. This includes both typical diseases experienced by the entire human population as well as those specific diseases to which pregnant or postpartum women are exposed. A well-known syndrome in the postpartum period is the so-called baby blues. According to the World Health Organisation, 80% of women may suffer from its symptoms. These include moderately decreased mood, irritability and emotional liability. Baby blues may appear during the first fortnight after childbirth. What is worth pointing out is that although baby blues itself does not need psychiatric treatment, the same symptoms, decreased mood, irritability and emotional liability may also indicate the beginnings of a severe illness: postpartum depression, where the psychiatrist’s support is essential. The prevalence of this much more acute illness equals around 7-19%, and its advanced symptoms are much more severe. Among others, the symptoms may include intrusive thoughts mainly related to hurting the baby, sleep disorders, feeling guilty or even suicidal thoughts. Therefore, low mood in women after childbirth should never be underestimated [13]. Hopefully, there are drug products that have proven to be safe and effective in the treatment of postpartum depression, which can even be used without cessation of breastfeeding. In each case, when the lactating woman or her family notices any sign of possible disease, she should immediately contact a physician who will be able to tailor the therapy precisely to her needs [14].
Summing everything up together, off-label use of drugs is a common practice in populations where there is poor evidence from clinical trials allowing the Regulatory Agencies to approve the drug product in particular indications, doses or formulations. The use of off-label drugs in pregnant and breastfeeding women presents unique challenges and considerations in pharmacotherapy. We need to bear in mind that populations such as newborns, infants, and pregnant women are highly vulnerable; the disposition of a pharmaceutical product within their organisms differs from the one in patients, which usually undergo tests in clinical trials. In such cases, but only based on the physician’s knowledge, starting therapy with such a product might be beneficial. By carefully evaluating the risks and benefits of off-label medication use, healthcare providers can ensure the safety of both the mother and the unborn or nursing child. Open communication, monitoring, and collaboration among healthcare teams are key in providing effective treatment options while prioritizing the well-being of women during pregnancy and lactation. Hopefully, awareness of the problem is developing, and there is a growing number of initiatives to explore this issue.
Sources:
- https://www.ema.europa.eu/en/glossary/label-use (29.04.2024)
- Niedźwiedź M, Skibińska M, Narbutt J, Lesiak A. Off-label medications in the treatment of hospitalized children with atopic dermatitis. Postepy Dermatol Alergol. 2023 Feb;40(1):72-77. doi: 10.5114/ada.2022.119967. Epub 2022 Oct 10. PMID: 36909909; PMCID: PMC9993195.
- Epstein RS, Huang SM. The many sides of off-label prescribing. Clin Pharmacol Ther. 2012 May;91(5):755-8. doi: 10.1038/clpt.2012.37. PMID: 22513307.
- Wittich CM, Burkle CM, Lanier WL. Ten common questions (and their answers) about off-label drug use. Mayo Clin Proc. 2012 Oct;87(10):982-90. doi: 10.1016/j.mayocp.2012.04.017. Epub 2012 Aug 6. PMID: 22877654; PMCID: PMC3538391.
- Costa HTML, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS One. 2018 Sep 25;13(9):e0204427. doi: 10.1371/journal.pone.0204427. PMID: 30252920; PMCID: PMC6155521.
- Wiles JR, Vinks AA, Akinbi H. Federal legislation and the advancement of neonatal drug studies. J Pediatr. 2013 Jan;162(1):12-5. doi: 10.1016/j.jpeds.2012.08.034. Epub 2012 Oct 27. PMID: 23110945; PMCID: PMC3723457.
- Stock SJ, Norman JE. Medicines in pregnancy. F1000Res. 2019 Jun 20;8:F1000 Faculty Rev-911. doi: 10.12688/f1000research.17535.1. PMID: 31249673; PMCID: PMC6587138.
- David AL, Ahmadzia H, Ashcroft R, Bucci-Rechtweg C, Spencer RN, Thornton S. Improving Development of Drug Treatments for Pregnant Women and the Fetus. Ther Innov Regul Sci. 2022 Nov;56(6):976-990. doi: 10.1007/s43441-022-00433-w. Epub 2022 Jul 25. PMID: 35881237; PMCID: PMC9315086.
- Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. doi: 10.1093/toxsci/kfr088. Epub 2011 Apr 19. Erratum in: Toxicol Sci. 2012 Feb;125(2):613. PMID: 21507989.
- García-Lino AM, Álvarez-Fernández I, Blanco-Paniagua E, Merino G, Álvarez AI. Transporters in the Mammary Gland-Contribution to Presence of Nutrients and Drugs into Milk. 2019 Oct 5;11(10):2372. doi: 10.3390/nu11102372. PMID: 31590349; PMCID: PMC6836069.
- Verstegen RHJ, Anderson PO, Ito S. Infant drug exposure via breast milk. Br J Clin Pharmacol. 2022 Oct;88(10):4311-4327. doi: 10.1111/bcp.14538. Epub 2020 Sep 13. PMID: 32860456.
- Rossato N. Breastfeeding and drugs. A common conflict. Arch Argent Pediatr. 2015 Jan;113(1):4-5. English, Spanish. doi: 10.5546/aap.2015.eng.4. PMID: 25622154.
- Dominiak M, Antosik-Wojcinska AZ, Baron M, Mierzejewski P, Swiecicki L. Recommendations for the prevention and treatment of postpartum depression. Ginekol Pol. 2021;92(2):153-164. doi: 10.5603/GP.a2020.0141. Epub 2021 Jan 15. PMID: 33448014.
- https://www.mp.pl/pytania/pediatria/chapter/B25.QA.2.1.64 (06.05.2024)