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Egg allergy usually develops within the first two years of life—precisely the period when most childhood vaccinations are administered. Because of this, children with egg allergy were often subjected to delays in vaccination, which increased their risk of contracting vaccine-preventable diseases. In the largest study to date, 171 children with egg allergy, including 24% with a history of anaphylaxis, underwent skin testing with the yellow fever vaccine. All of them were subsequently vaccinated regardless of skin test results, with no allergic reactions observed. Why Are These Results Important? The yellow fever vaccine is grown in fertilized chicken eggs, which can leave residual egg proteins in the final product. Compared with other vaccines, the amount of egg protein in the yellow fever vaccine is considered significant. Until now, this raised concerns about its safety for individuals with egg allergy. Although some vaccines contain trace amounts of egg protein (e.g., influenza, measles, mumps, rubella, and rabies vaccines), the concentrations are too low to cause allergic reactions—even in individuals with severe egg allergy. Based on current evidence, routine testing or delaying vaccination due to egg allergy is no longer recommended. This applies to all vaccines. Physicians should always be prepared for the rare occurrence of allergic reactions after administration of any vaccine, but no special precautions are required for individuals with egg allergy. Conclusion Egg allergy is no longer a reason to delay or withhold any vaccination. Timely immunization remains essential for protecting health. References Ramírez-Giraldo RH, et al. No Yellow Fever Vaccine Reactions in IgE-Mediated Egg Allergic Patients.  Int Arch Allergy Immunol. 2025;186(1):52–58. doi:10.1159/000539505. UpToDate.  Practice Changing Updates.

Over the past few decades, the world has faced growing challenges in treating invasive fungal infections. Increasing resistance, expanding high-risk populations, and the limited number of effective drugs have created a need for new antifungal agents. Until now, standard antifungal therapy has relied on three main classes: azoles (voriconazole, posaconazole, isavuconazole), echinocandins (caspofungin, micafungin, anidulafungin), and amphotericin B. While effective, these drugs have significant limitations: Azoles  are associated with numerous CYP-mediated interactions and hepatotoxicity. Amphotericin B  is nephrotoxic and requires parenteral administration. Echinocandins  have a limited spectrum of activity and are also available only intravenously. New Antifungals After more than 20 years of stagnation, several promising antifungal agents are now in late-stage clinical development. 1. Fosmanogepix (Manogepix) Fosmanogepix is a prodrug converted in the body to manogepix, an inhibitor of the Gwt1 enzyme. This disrupts the synthesis of GPI-anchored proteins in the fungal cell wall, compromising virulence and growth. It has broad-spectrum activity, including resistant strains of Candida spp. , Aspergillus spp. , Fusarium spp. , and some Mucorales . In phase II trials, it showed good tolerability and 80% efficacy in treating invasive candidiasis. It is being developed in both oral and parenteral formulations. 2. Ibrexafungerp The first antifungal from the triterpenoid class, ibrexafungerp inhibits 1,3-β-D-glucan synthesis, similar to echinocandins but at a different binding site, reducing cross-resistance. It is approved for vulvovaginal candidiasis and, in phase III trials, has shown efficacy against invasive candidiasis and aspergillosis. Advantages include oral administration and good tissue penetration. Oral and parenteral formulations are in development. However, as a CYP3A4 substrate, it carries potential for drug interactions. Animal studies suggest teratogenic risk, so in women of childbearing potential it must be prescribed with mandatory contraception. 3. Olorofim A member of the novel orotomide class, olorofim inhibits the enzyme dihydroorotate dehydrogenase (DHODH), disrupting pyrimidine synthesis. Its activity is limited to molds ( Aspergillus spp. , Lomentospora , Scedosporium ), but it shows exceptional potential in multidrug-resistant infections. Clinical trials demonstrate safety and potential use for infections resistant to all other therapies. As a CYP3A4 substrate, it may interact with other drugs. 4. Opelconazole This new triazole has been optimized for inhaled administration, designed for the treatment of pulmonary aspergillosis. Inhaled delivery achieves high local concentrations in the lungs with minimal systemic exposure and side effects. Although inhaled, as a CYP3A4 substrate it still carries a potential for drug interactions. 5. Rezafungin A second-generation echinocandin, rezafungin has an extended half-life, allowing once-weekly dosing. It demonstrates strong activity against Candida spp.  (including C. auris ) and Aspergillus spp. , and is being tested for prophylaxis in immunocompromised patients. Phase II data show good tolerability and high efficacy. 6. Oral Formulation of Amphotericin B An oral formulation of amphotericin B is currently under clinical investigation for the treatment of cryptococcal meningitis. Compared to parenteral amphotericin B, the oral formulation has the potential for reduced nephrotoxicity and electrolyte disturbances. Amphotericin B retains its broad spectrum of activity, covering Candida spp. , Aspergillus spp. , Mucorales , and Cryptococcus . Conclusion The development of these new antifungals marks a significant step forward in the management of invasive fungal infections. With novel mechanisms of action, availability in both oral and parenteral formulations, pharmacokinetic advantages, and broad activity spectra, their anticipated arrival on the market will be of great importance to clinical practice. Find the full article in Pharmaca , Issue 2–2025. References Hoenigl M, et al. The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs.  2021 Oct;81(15):1703-1729. doi:10.1007/s40265-021-01611-0. PMID: 34626339; PMCID: PMC8501344. Vanbiervliet Y, et al. Correction: Review of the novel antifungal drug olorofim (F901318). BMC Infect Dis.  2024 Dec 12;24(1):1395. doi:10.1186/s12879-024-10295-2. Erratum for: BMC Infect Dis.  2024 Nov 7;24(1):1256. doi:10.1186/s12879-024-10143-3. PMID: 39668372; PMCID: PMC11636042. Boulware DR, et al. Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial. Clin Infect Dis.  2023 Dec 15;77(12):1659–1667. doi:10.1093/cid/ciad440.

Dear colleagues, It is our great pleasure to invite you to the 2nd Croatian Congress of Clinical Pharmacology and Therapeutics with International Participation. 📅 September 18–20, 2025 | Opatija, Croatia In a time of increasingly complex therapeutic decisions, limited resources, and the rapid development of new medicines, clinical pharmacology plays a key role in ensuring rational, effective, and safe pharmacotherapy. The Congress will bring together experts from diverse fields to discuss current challenges and opportunities for improving therapeutic practice. Congress theme:   Clinical Pharmacology: Rational Therapy for Today’s Challenges Key topics: ✔ Rational use of medicines ✔ Challenges in treating special populations ✔ Pharmacoeconomics and sustainability ✔ Oncology and personalized medicine ✔ Interdisciplinary collaboration and evidence-based clinical practice We are proud to highlight collaboration with the British Pharmacological Society in organizing a joint symposium dedicated to the challenges of treating rare diseases, addressing regulatory, clinical, and social aspects. Workshop: 🔹 Designing different types of clinical trials 🌐 More information, preliminary program, and registration:👉 https://www.clinicalpharmacologycroatia.org/hr 📅 Save the date: September 18–20, 2025 – see you in Opatija! Warm regards, Prof. Dinko Vitezić, MD, PhD – Congress President Prof. Suzana Mimica, MD, PhD – Congress Vice-President Assist. Prof. Viktorija Erdeljić Turk, MD, PhD – Congress Secretary

Arterial hypertension, often called the “silent killer,” remains one of the leading public-health challenges of the 21st century. Despite the availability of effective therapies, blood pressure (BP) control globally remains unsatisfactory. Recent data indicate that fewer than 25% of patients achieve target BP values, highlighting the complexity of the problem, which includes clinical inertia, poor patient adherence, and insufficient health literacy. Pathophysiological Basis and Diagnostic Approach Most patients (90–95%) have primary, or essential, hypertension arising from a complex interaction of genetic predisposition and environmental factors such as obesity, salt intake, stress, and physical inactivity. Secondary hypertension, though less common, must be ruled out in atypical cases or resistant hypertension, particularly in younger patients. Accurate diagnosis requires standardized BP measurement; 24-hour ambulatory blood pressure monitoring (ABPM) and home BP monitoring. Laboratory evaluation includes assessment of renal function, glucose and lipid metabolism, and evaluation of target-organ function. Non-pharmacological Measures Non-pharmacological interventions should be the initial and ongoing component of hypertension management at all stages and in all patients. Their effectiveness is scientifically proven and recommended in all international guidelines. Recommended measures and effects: Reduce salt intake:  <2.3 g sodium/day (ideally <1.5 g); BP reduction ~5–6 mmHg. DASH diet (Dietary Approaches to Stop Hypertension):  rich in fruits, vegetables, whole grains; low in saturated fats; BP reduction ~8–14 mmHg. Physical activity:  at least 30 minutes of moderate activity most days (e.g., brisk walking); BP reduction ~4–9 mmHg. Weight loss:  each kilogram lost may reduce BP by ~1 mmHg. Limit alcohol intake:  up to 2 drinks/day for men and 1 drink/day for women (a standard drink ≈ 10 g ethanol, e.g., 100 ml wine, 250 ml beer, 30 ml spirits). Smoking cessation:  markedly reduces cardiovascular risk (although not directly BP). Stress reduction and relaxation techniques  (e.g., meditation, biofeedback) may be helpful in some patients. In patients with low to moderate cardiovascular risk, these measures may suffice to achieve target BP. In high-risk patients (e.g., diabetes, chronic kidney disease, prior myocardial infarction), pharmacotherapy is initiated earlier—at BP ≥130/80 mmHg. When to Start Pharmacologic Therapy? Indications for initiating drug therapy: BP ≥140/90 mmHg  in individuals with low cardiovascular risk after attempts at non-pharmacological measures. BP ≥130/80 mmHg  in high-risk patients, including: Diabetes mellitus Chronic kidney disease (GFR <60 ml/min) Prior myocardial infarction or stroke Significant left ventricular hypertrophy Target BP values: <130/80 mmHg  for most patients <140/90 mmHg  for older and frail patients when lower values are not well tolerated <120 mmHg systolic  — recommended only in U.S. guidelines for selected high-risk patients (based on SPRINT and STEP); the 2024 European guidelines  do not support universal application and emphasize careful patient selection. Pharmacotherapy of Hypertension First-line drug classes include: Thiazide diuretics (e.g., chlorthalidone, indapamide) ACE inhibitors (e.g., lisinopril, ramipril) Angiotensin II receptor blockers (ARBs) (e.g., losartan, valsartan) Calcium channel blockers (CCBs) (e.g., lacidipine, amlodipine, diltiazem) Beta-blockers (e.g., bisoprolol, nebivolol) Drug selection is based on comorbidities, age, sex, and individual tolerability. For example, in diabetics with renal impairment, ACEIs/ARBs are recommended for their nephroprotective effects. A two-drug combination (e.g., ACEI + CCB) is often needed at the outset, especially when BP >150/100 mmHg. Special Populations and Personalized Approach Pregnancy requires special consideration; safe options include methyldopa, labetalol, and nifedipine, while ACEIs and ARBs are contraindicated. In older adults, begin therapy cautiously with lower doses and gradual titration. In patients with GFR <30 ml/min, thiazide diuretics are avoided due to reduced efficacy; loop diuretics are preferred when a diuretic is indicated. Resistant Hypertension and Emergencies Resistant hypertension is defined as BP ≥130/80 mmHg despite three antihypertensives (including a diuretic). Management includes excluding secondary causes, assessing adherence, and considering add-on therapy (e.g., spironolactone) or renal denervation. Hypertensive crisis denotes a sudden rise in BP >180/120 mmHg with or without target-organ damage. Crises are classified as urgencies (no organ damage) and emergencies (with organ damage). Treatment involves controlled, gradual BP reduction to avoid ischemia and organ hypoperfusion. New Therapeutic Approaches Early and more intensive BP lowering Trials SPRINT, STEP, BPROAD show benefits of aggressive systolic BP lowering to <120 mmHg in high-risk patients. Benefits: reduced myocardial infarction, stroke, and mortality. Risks: hypotension, syncope, renal insufficiency. Not yet routinely adopted in Europe. “Polypill” concept Combining multiple antihypertensives in one tablet. Advantages:  better adherence, lower treatment cost. Suitable for patients with multiple comorbidities, polypharmacy, and poor adherence. Personalized medicine Targeted drug selection based on pharmacogenetics, comorbidities, and phenotype. Example: aldosterone/renin ratio assessment in resistant hypertension. Use of SGLT2 inhibitors Dapagliflozin, empagliflozin lower BP by ~3–5 mmHg independent of glycemia and provide additional cardioprotective effects. Particularly useful in diabetes and in patients with cardiovascular and renal disease. Mineralocorticoid receptor antagonists (MRAs) Spironolactone and eplerenone are effective in resistant hypertension. Caution: may cause hyperkalemia and gynecomastia. Renal denervation A minimally invasive intervention that reduces renal sympathetic innervation. Has shown favorable effects in patients with resistant hypertension. Conclusion Successful hypertension management requires an integrated approach encompassing patient education, regular follow-up, lifestyle modification, and optimal pharmacotherapy. Understanding modern therapeutic strategies is essential for every clinician, given the prevalence, chronic course, and serious health consequences of hypertension. Effective treatment involves more than prescribing medications: it requires thorough cardiovascular risk assessment, individualized therapy, implementation of non-pharmacological measures, and close monitoring of adherence and treatment response. References 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Available at: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Elevated-Blood-Pressure-and-Hypertension Li X, Zhang J, Xing Z, Liu Q, Zhou S, Xiao Y. Intensive blood pressure control for patients aged over 60: A meta-analysis of the SPRINT, STEP, and ACCORD BP randomized controlled trials. Maturitas.  2023 Jun;172:52–59. doi:10.1016/j.maturitas.2023.04.009. Seidu S, Willis H, Kunutsor SK, Khunti K. Intensive versus standard blood pressure control in older persons with or without diabetes: a systematic review and meta-analysis of randomised controlled trials. J R Soc Med.  2023 Apr;116(4):133–143. doi:10.1177/01410768231156997. Bi Y, Li M, Liu Y, Li T, Lu J, Duan P, Xu F, Dong Q, Wang A, Wang T, Zheng R, Chen Y, Xu M, Wang X, Zhang X, Niu Y, Kang Z, Lu C, Wang J, Qiu X, Wang A, Wu S, Niu J, Wang J, Zhao Z, Pan H, Yang X, Niu X, Pang S, Zhang X, Dai Y, Wan Q, Chen S, Zheng Q, Dai S, Deng J, Liu L, Wang G, Zhu H, Tang W, Liu H, Guo Z, Ning G, He J, Xu Y, Wang W; BPROAD Research Group. Intensive Blood-Pressure Control in Patients with Type 2 Diabetes. N Engl J Med.  2025 Mar 27;392(12):1155–1167. doi:10.1056/NEJMoa2412006. Epub 2024 Nov 16.

Breastfeeding is universally accepted as the most desirable method of infant nutrition. However, it is sometimes discontinued prematurely due to concerns that medications taken by the mother may harm the child. The amount of a drug that passes into breast milk depends on its concentration in maternal serum and on the drug’s pharmacological properties. When prescribing medications to a breastfeeding mother, preference should always be given to those that pose the lowest possible risk to the infant. Ideally, dosing should be planned immediately before the infant’s longest sleep period. Physicians should rely on verified sources of information. One of the most reliable and accessible resources is LactMed , a database maintained by the U.S. National Library of Medicine. This free online platform provides peer-reviewed, regularly updated information on the safety of numerous medications during breastfeeding. Transfer of Drugs Into Breast Milk Drugs enter breast milk primarily by diffusion from maternal serum, meaning the concentration in milk generally reflects the plasma concentration. Only a small number of drugs are actively transported into milk. Most drugs diffuse back into the maternal circulation as plasma levels decline. Unlike pregnancy, where drugs cross the placenta, during breastfeeding the key factor is the infant’s ability to absorb the drug through the gastrointestinal tract. The amount of drug received depends on its concentration in milk, the volume of milk consumed, and the infant’s absorption capacity. In the early postpartum period, drugs pass into milk more easily because of wider gaps between the alveolar cells of the mammary gland. However, since colostrum is produced in small quantities, infant exposure is limited. Topical medications are generally safer than oral ones, though products applied directly to the nipple can pose a risk if not removed before feeding. The infant’s health also plays a role. Premature and ill newborns are more vulnerable because of immature metabolic and elimination pathways. Strategies to reduce exposure include dosing immediately after breastfeeding and choosing drugs with poor oral absorption, low lipophilicity, and high protein binding, as such drugs are less likely to pass into milk. Relative Infant Dose (RID) The Relative Infant Dose (RID)  estimates the amount of drug an infant receives through breast milk in relation to the maternal dose (mg/kg/day). It is calculated as: RID (%) = (dose in milk mg/kg/day) / (maternal dose mg/kg/day) × 100 In clinical practice, an RID of less than 10% is generally considered safe, i.e., unlikely to cause clinically significant infant exposure. For most drugs, RID is well below 1%. If the RID exceeds 10%, a theoretical risk exists, requiring a careful benefit–risk assessment. Treatment of Selected Conditions During Breastfeeding Table 1. Recommendations for medication use during breastfeeding Condition Recommended drugs Acceptable alternatives Use with caution Avoid Allergic rhinitis Cromolyn, decongestants, topical corticosteroids, saline Loratadine Pseudoephedrine — Analgesics Paracetamol, ibuprofen, topical diclofenac — Opioids Codeine, hydromorphone, meperidine, naproxen, oxycodone, tramadol Antibiotics Penicillins, cephalosporins Macrolides, fluoroquinolones Clindamycin, TMP/SMX, metronidazole, aminoglycosides, doxycycline — Anxiety Lorazepam — Clonazepam — Asthma Inhaled bronchodilators, inhaled corticosteroids, montelukast, prednisolone Omalizumab Theophylline — ADHD Methylphenidate Amphetamines Atomoxetine, clonidine, guanfacine — Contraception Non-hormonal methods, progestin-only contraceptives — Combined oral contraceptives — Depression Paroxetine, sertraline Desvenlafaxine, duloxetine, fluvoxamine, venlafaxine Fluoxetine — Diabetes mellitus Insulin, metformin, 2nd gen. sulfonylureas — DPP-4 inhibitors, GLP-1 agonists — Hypertension ACE inhibitors, calcium channel blockers, diuretics — Beta-blockers, ARBs — Analgesics Ibuprofen and paracetamol are first-line analgesics during breastfeeding, due to low concentrations in breast milk and proven safety in infants. Long-term naproxen use is not recommended, as its long half-life is associated with risks of bleeding, anemia, and vomiting in infants. NSAIDs such as meloxicam, piroxicam, celecoxib, and etoricoxib are also not recommended due to limited safety data. Local and topical anesthetics (e.g., lidocaine patches, infiltration anesthesia) are considered safe. If strong pain control requires oral opioids, hydrocodone or morphine are preferred due to better-known safety profiles. Breastfeeding should ideally take place before maternal dosing to minimize infant exposure. Since infants are sensitive to even small opioid doses, opioids should be used at the lowest effective dose, for the shortest possible time, and avoided in combination with other sedatives to reduce the risk of sedation or respiratory depression in the infant. Antibiotics Most commonly prescribed antibiotics are compatible with breastfeeding. Penicillins and cephalosporins are first-line agents. However, all antibiotics may cause allergic reactions or diarrhea in infants due to changes in gut flora. Cases of hematochezia have been reported in infants exposed to IV clindamycin via breast milk. TMP/SMX should be avoided in infants with hyperbilirubinemia, illness, prematurity, or stress due to the risk of kernicterus. TMP/SMX and nitrofurantoin should be avoided during the first month of life and in infants with G6PD deficiency due to the risk of hemolysis. Metronidazole exposure has been linked to candidiasis and diarrhea in infants. Calcium in breast milk may reduce absorption of fluoroquinolones and doxycycline. Fluoroquinolones have traditionally been avoided due to concerns about joint toxicity, though newer data suggest this risk is minimal. Some antibiotics may alter milk taste, potentially reducing intake. Mental Health and Breastfeeding When psychiatric disorders occur during breastfeeding, the priority is effective maternal treatment, often with the same medications used during pregnancy. Most antidepressants are compatible with breastfeeding, but risk–benefit assessments are essential. Stimulants (e.g., for ADHD) may reduce milk supply and should be used cautiously, with infant monitoring for irritability or poor weight gain. Hypertension Antihypertensive drugs are generally safe during breastfeeding. Methyldopa, a first-line agent in pregnancy, may be continued during lactation. Calcium channel blockers transfer minimally into milk. Diuretics at antihypertensive doses do not affect lactation significantly. ACE inhibitors also have minimal transfer. ARBs are highly protein-bound and unlikely to transfer significantly, but safety data are lacking, so they are not recommended for neonates or preterm infants until further studies are available. Beta-blockers vary in milk excretion; labetalol and metoprolol are considered safe with minimal milk transfer, but caution is required in premature infants. Diabetes Insulin, metformin, and second-generation sulfonylureas are preferred. Newer agents (SGLT2 inhibitors, GLP-1 agonists, DPP-4 inhibitors) lack sufficient safety data and are generally not recommended during breastfeeding. Respiratory Disorders Local and inhaled therapies (e.g., inhaled corticosteroids, bronchodilators, nasal sprays) have minimal systemic effects and are safe. Loratadine may be used for allergy symptoms. Herbal Products Herbal galactagogues (fenugreek, fennel, milk thistle) are commonly used, but evidence for efficacy is limited. Quality control is inconsistent, raising concerns about contamination or unknown ingredients. Some herbs (coffee, yohimbine, sage, peppermint, parsley, chasteberry, jasmine) may harm the infant or reduce milk supply. Information on herbal safety can be found in LactMed and e-Lactancia, though data are often limited due to a lack of clinical trials in breastfeeding women. Contraception During Breastfeeding In the first 4–6 weeks postpartum, non-hormonal methods (barrier methods, copper IUD) are preferred. Combined oral contraceptives (estrogen + progestin) may reduce milk production and increase thrombosis risk, and are not recommended in early postpartum. Progestin-only methods (e.g., levonorgestrel IUD, etonogestrel implant) are safer and compatible with breastfeeding. Reliable Sources of Information Understanding pharmacokinetics and pharmacodynamics is critical for safe prescribing in breastfeeding. Clinicians should rely on up-to-date, evidence-based resources such as: LactMed  (NIH, free database) e-Lactancia  (Spanish/English, simple risk summaries) Medications and Mothers’ Milk  (Thomas Hale – textbook, app, database) Drugs.com  (updated patient information) MotherToBaby.org  (educational fact sheets) The U.S. Pregnancy and Lactation Labeling Rule (PLLR) , implemented in 2014, requires clearer labeling on drug safety in pregnancy and breastfeeding, though many product labels remain outdated. Reviews show that breastfeeding safety information varies in restrictiveness. Manufacturer labels are often conservative, while LactMed provides less restrictive, evidence-based assessments. How to Minimize Infant Risk General recommendations Avoid unnecessary medication use whenever possible. Drugs safe for infants are usually safe for breastfeeding mothers. Drugs safe in pregnancy are not automatically safe in breastfeeding. Use reliable sources to check drug safety in breast milk. Prefer local/topical therapy when possible (except on the nipple). Drug selection Choose drugs with established safety data in breastfeeding. Favor drugs with low fat solubility, poor oral absorption, short half-life, and high protein binding. Dosing For once-daily drugs, dose immediately before the infant’s longest sleep (usually after evening feeding). For multiple daily doses, feed the infant immediately before each dose. Use caution with drugs with long half-lives (e.g., diazepam). In such cases, assess carefully whether treatment is truly necessary. Conclusion Most medications are compatible with breastfeeding, especially with careful selection and individualized adjustments. Before advising mothers to interrupt breastfeeding or postpone treatment, clinicians should consult authoritative sources and weigh all options. Healthcare professionals play a crucial role in informing mothers and dispelling unfounded fears. Evidence-based decision-making ensures the safety and well-being of both mother and child. References: NIH. LactMed® Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/?term=lactmed van den Oever HL, Versteegh FG, Thewessen EA, et al. Ciprofloxacin in preterm neonates: Case report and review of the literature. Eur J Pediatr.  1998;157:843–5. Spencer JP, Thomas S, Trondsen Pawlowski RH. Medication Safety in Breastfeeding. Am Fam Physician.  2022 Dec;106(6):638–644. PMID: 36521462. Hotham N, Hotham E. Drugs in breastfeeding. Aust Prescr.  2015;38:156–59. doi:10.18773/austprescr.2015.056

Older patients with hypertension are at high risk of cardiovascular complications, making appropriate antihypertensive therapy especially important in this population. However, randomized clinical trials often exclude patients with marked frailty, as adverse effects of antihypertensive therapy are more common in these individuals. Several observational studies have shown that in frail patients, low blood pressure is associated with increased cardiovascular morbidity and mortality, particularly in those receiving antihypertensive therapy. In the observational PARTAGE study, which included nursing home residents over 80 years of age with hypertension, overall mortality was found to be twice as high among participants with systolic blood pressure below 130 mmHg who were taking more than one antihypertensive, compared to other participants. This finding from the PARTAGE study raises an important question about the management of hypertension in older patients with pronounced frailty. The latest European hypertension guidelines emphasize the need to tailor therapy to the degree of frailty and recommend considering gradual reduction of antihypertensive therapy in patients with low blood pressure. However, evidence on the benefits and risks of discontinuing antihypertensive drugs in older adults remains limited. There is consensus that clinical research should focus on populations where uncertainty about the risks and benefits of antihypertensive therapy is greatest, such as frail individuals, the very elderly, and those receiving multiple medications simultaneously. Recently, the results of the RETREAT-FRAIL (Reduction of Antihypertensive Treatment in Frail Patients) study were published. This was a pragmatic, interventional, randomized trial that evaluated the effect of protocol-guided, stepwise reduction of antihypertensive therapy, compared with usual care, on overall mortality among nursing home residents aged 80 years or older with pronounced frailty, systolic blood pressure below 130 mmHg, and treatment including at least two antihypertensives. In this multicenter, randomized, controlled trial conducted in France, participants were randomized in a 1:1 ratio to either protocol-based gradual reduction of antihypertensive therapy or usual care (control group). Patients were followed for up to 4 years. The primary outcome was death from any cause. Secondary outcomes included changes in the number of antihypertensive medications from baseline to final visit and changes in systolic blood pressure during follow-up. Results of the RETREAT-FRAIL Study A total of 1,048 patients were randomized: 528 to the antihypertensive reduction group and 520 to the control group. The estimated median follow-up was 38.4 months. Between baseline and the final visit, the mean (±SD) number of antihypertensives decreased from 2.6±0.7 to 1.5±1.1 in the reduction group and from 2.5±0.7 to 2.0±1.1 in the control group. The adjusted mean difference between groups (reduction group minus control group) in systolic blood pressure change during follow-up was 4.1 mmHg (95% confidence interval [CI], 1.9 to 5.7). All-cause mortality occurred in 326 patients (61.7%) in the reduction group and 313 patients (60.2%) in the control group (adjusted hazard ratio 1.02; 95% CI, 0.86 to 1.21; P=0.78). There were no significant differences in adverse events between the groups. Conclusion In frail nursing home residents over 80 years of age who were taking more than one antihypertensive and had systolic blood pressure below 130 mmHg, a strategy of gradual reduction of antihypertensive therapy did not result in lower overall mortality compared with usual care. In conclusion, this trial did not confirm the authors’ hypothesis that stepwise reduction of antihypertensive therapy in this population would lead to a 25% reduction in overall mortality compared with usual care. Adapted from: Benetos A, et al; RETREAT-FRAIL Study Group. Reduction of Antihypertensive Treatment in Nursing Home Residents. N Engl J Med. 2025 Aug 29. doi: 10.1056/NEJMoa2508157.

Women most commonly take metformin for diabetes or polycystic ovary syndrome. Metformin crosses the placenta and reaches fetal plasma concentrations comparable to those in the mother. Animal studies have not shown any harmful effects during pregnancy, embryonic or fetal development, birth, and postnatal development. In 2022, based on the results of the CLUE study, designed and sponsored by Merck pharmaceutical company, and other safety data, the Summary of Product Characteristics for metformin was modified to include the possibility of considering metformin use during pregnancy, as monotherapy or in combination with insulin. Data on the effects of metformin on pregnancy and pregnancy outcomes are still limited. The latest safety data for metformin during pregnancy come from a cohort study conducted in Finland, the CLUE study, with results published in 2022. The study followed pregnancy outcomes in women exposed to metformin only (n=3967), insulin only (n=5273), and a combination of metformin and insulin (n=889) from 2004 to 2016. The primary outcomes were child obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and developmental disorders (motor, social). The study did not find an increased risk associated with metformin exposure (alone or in combination with insulin) compared to insulin use alone. However, there was an increased risk of low birth weight (a secondary outcome) with metformin compared to insulin, suggesting caution in pregnancies with a risk of fetal malnutrition. A meta-analysis of studies published up to 2014 did not find an increased risk of malformations in children of around 1000 women exposed to metformin during the first trimester of pregnancy. Another cohort study presented as a congress abstract in 2021, which included around 3000 pregnancies with metformin exposure, did not find an increased risk of congenital malformations following metformin use during pregnancy. However, another cohort study with 392 pregnancies exposed to metformin during the first trimester found a higher risk of congenital malformations in women exposed to metformin (5.1% compared to 2.1% in the control group). The authors explained this difference by an increase in intrinsic risk due to diabetes. Two published case-control studies found a possible association between metformin use in the first trimester and an increased risk of congenital malformations (cardiac, pulmonary) in one study and an increased risk of atrial septal defect and limb defects in the other study where metformin was used for infertility treatment. Contradictory study results may be attributed to different indications for use, study design, and overall do not support clear conclusions about potential risks. In clinical practice, available data on monitoring pregnancy outcomes in women taking metformin during pregnancy do not suggest a significant risk of malformations with metformin use in the first trimester, but they do not exclude the possibility of rare malformations. Longer-term data on pregnancy outcomes are needed to better assess the long-term risk of metformin use in early pregnancy. If a pregnant woman requires treatment for elevated glucose levels, insulin remains the first-line treatment since insulin does not cross the placenta. If metformin use is considered, it is important to inform the pregnant woman about its benefits and the still present uncertainties related to potential risks. Literature: 1. Prescrire Redaction. Metformin during pregnancy: possible risk of malformations. Rev Prescrire 2023; 23: 46-8. 2. Panchaud A, Rousson V, Vial T, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services. Br J Clin 2018; Pharmacol 2018 ; 84: 568–78. 3. Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Research and Care 2022;10:e002363. 4. Nguyen L, Chan SY, Teo AKK. Metformin from mother to unborn child - Are there unwarranted effects? EBioMedicine 2018; 35: 394-404.

Immunotherapy has become the primary treatment for patients with various types of cancer, offering the potential to extend their survival. Typically, immunotherapy is administered until disease progression or unacceptable toxicity, or up to the recommended maximum duration in patients without disease progression. Recently, the criteria for the use of PD-1/PD-L1 immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), durvalumab (Imfinzi), and atezolizumab (Tecentriq), have been modified by the Croatian Health Insurance Fund (HZZO). According to the new criteria, the duration of treatment is limited to a maximum of 24 months for all drugs except for adjuvant treatment in melanoma (nivolumab, pembrolizumab), where the duration is limited to one year. The optimal duration of immunotherapy in cancer treatment is still not well-established. Guidelines from ESMO (European Society for Medical Oncology) and NCCN (National Comprehensive Cancer Network) recommend a duration of two years in the first-line setting. However, most clinical trials have arbitrarily limited the duration to two years, and there is a lack of definitive clinical studies to determine the optimal duration. The main efficacy outcomes monitored in clinical studies with immunotherapy are progression-free survival (PFS) and overall survival (OS). Some evidence suggests that patients treated with immunotherapy for one year may have a shorter PFS compared to those treated for a longer period. However, data from real-world studies indicate that longer treatment duration may lead to better survival rates, with the risk of disease relapse after treatment cessation depending on the initial response achieved. The decision to continue or stop immunotherapy after two years is still a matter of debate among healthcare professionals. Some argue that stopping treatment after achieving a complete or partial response might be appropriate, especially considering the potential toxicity and costs associated with long-term treatment. Prospective clinical trials are currently underway to explore early discontinuation criteria and biomarkers that could help quantify the risk of disease recurrence. These studies aim to determine the optimal duration of treatment and indications for discontinuation while taking into account patient response and other factors. The choice between continuous immunotherapy and a fixed duration is challenging, as toxicity and costs play significant roles. While most side effects occur within the first 6-9 months of treatment, some patients may experience severe toxicity later on. Additionally, the financial burden of long-term immunotherapy could strain healthcare systems and impact access to care. In conclusion, the optimal duration of immunotherapy remains uncertain, and an arbitrary cutoff of two years may not be appropriate for all patients. Individualized treatment decisions should consider patient response, toxicity, quality of life, and the potential for long-term disease control. Further research is needed to identify the best approach to immunotherapy duration and its impact on overall survival. Literature: 1. Waterhouse DM, Garon EB, Chandler J, et al. Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153. J Clin Oncol 2020;38: 3863-73. 2. Ghisoni E, Wicky A, Bouchaab H, et al. Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy. Eur J Cancer 2021; 149: 153-64. 3. Marron TU, Ryan AE, Reddy SM, et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J Immunother Cancer 2021; 9: e001901. oi: 10.1136/jitc-2020-001901. PMID: 33653801; PMCID: PMC7929825. 4. Yin J, Song Y, Tang J, Zhang B. What is the optimal duration of immune checkpoint inhibitors in malignant tumors? Front Immunol. 2022 Sep 26;13:983581. doi: 10.3389/fimmu.2022.983581. PMID: 36225926; PMCID: PMC9548621. 5.Geier M, Descourt R, Corre R, et al. Duration of nivolumab for pretreated, advanced non-small-cell lung cancer. Cancer Med 2020; 9: 6923-32.

Statins have an important role in the treatment and prevention of cardiovascular disease, but the question of uncertainties regarding their risk-benefit ratio for elderly patients is often raised. When initiating statin therapy it is important to take into account age-related pharmacodynamic and pharmacokinetic changes that increase the risk of statin adverse reactions. Also, possible drug-drug interactions, co-morbidities that shorten life expectancy and assumed therapy adherence should be taken into account. Population of the elderly patients is very heterogenous in terms of chronological age, ageing-related biological changes, co-morbidities and indications for a statin (primary or secondary prevention). For statins in secondary prevention, there is consistency among international guidelines and relevant publications that statins are indicated regardless of the age. Although an individual approach for the use of statins in primary prevention according to the cardiovascular (CV) risk is recommended, many international guidelines recommend starting statin therapy in all patients under 75 years of age with elevated CV risk. Chronological age > 75 years does not represent per se a contraindication to initiate statin in primary prevention but parameters as co-morbidities, frailty, life expectancy and expected drug adherence have to be considered. In conclusion, chronological age is not a reason to avoid statins because patients with the same age could significantly differ regarding their health status and vitality/frailty. The question a clinician should ask himself is whether the expected time to benefit from statin treatment will be longer than the expected time to harm (adverse effects) or the expected patient's life expectancy. You can read more about this topic in the next issue of Pharmaca (in Croatian) in the article authored by Suzana Mimica and Zvonimir Čagalj. #statins #sideeffects #adverseeffects #elderly #age #pharmacotherapy #clinicalpharmacology #rationalpharmacotherapy #evidencebasedmedicine #insurance #reimbursement