Marketing Authorisation Holders (MAH) should report to competent authorities (CA) adverse drug reactions received spontaneously or identified from the literature. Both sources of information are important for evaluating drug safety. Safety cases from the medical literature may have clinical significance, especially for rare events. Because they may not be detected in clinical trials prior to drug approval. Such messages may raise awareness of potential safety signals and may trigger further pharmacovigilance actions. Spontaneous ADR reports are the basis of any pharmacovigilance system, but they should be supported by adequate regular literature monitoring. Given the low level of spontaneous ADR reporting to the CA by health professionals, regular medical literature monitoring is a powerful tool for obtaining valuable safety information. Therefore, it is necessary to identify adverse drug reactions in the local medical literature.
The role of local medical literature in the ADR detection
One example of the importance of regular medical literature monitoring is the report on “flaccid iris syndrome”. It was first described in the literature in 2005. The authors of the article reported 26 cases of this intraoperative syndrome in patients after taking the drug tamsulosin. But they did not report any of them to the Competent Authority (CA). Physicians appear to have been more academically oriented, publishing this medically important phenomenon without reporting to the CA. Subsequently, “flaccid iris syndrome” was included in the Summary of Product Characteristics (SmPC) of tamsulosin, which is apparently related to several published reports of this syndrome in the medical literature. Sometimes MAHs consider that important drug safety information, including ICSRs, is published only in journals indexed in large bibliographic databases. Contrary to this opinion we provide some examples of importance of local nonindexed medical literature monitoring for safety cases identification.
Adverse reactions to antibiotics in the local literature
The DrugCard platform found an article in the Ukrainian Pulmonary Journal describing ADR cases in patients caused by antibacterial drugs use. The first safety case describes the patient who developed dizziness a few days after taking levofloxacin, which consequently led to a fall, resulting in a femoral neck fracture. In the second case, the patient was prescribed moxifloxacin and ceftazidime in the postoperative period. On the 5th day, diarrhea appeared, which was evaluated as antibiotic-associated diarrhea, and signs of dynamic obstruction were observed. After a series of hypertensive enemas, the patient’s condition improved somewhat. But after a day it deteriorated sharply: stool more than 30 times/day, severe abdominal pain, severe weakness, edema of the extremities, bilateral pleurisy, ascites, leukocytosis, hypoproteinemia and hypoelectrolytemia. The diagnosis of pseudomembranous colitis was established and the therapeutic tactic was radically changed. After 1 month the patient was discharged in satisfactory condition. Also, the authors indicate that perhaps this complication could have been avoided because the patient had a medical history of cephalosporins-associated diarrhea.
The case of toxic-epidermal necrolysis for hydroxychloroquine in the local literature
A case of serious life-threatening ADR was identified by the DrugCard platform in the publication “Ukrainian Rheumatology Journal“. The authors describe a clinical case of toxic epidermal necrolysis (TEN) in a patient with systemic lupus erythematosus (SLE) associated with hydroxychloroquine use. According to EULAR recommendations, the patient was prescribed methylprednisolone, hydroxychloroquine, calcium supplements with vitamin D for the treatment of SLE, and antihypertensive drugs were continued. 7 days after discharge from the hospital and on the 11th day from the start of hydroxychloroquine use, the patient developed a profuse spotty rash on the upper torso. Further development of the rash and its spread was not provoked by insolation and was not accompanied by the aggravation of lupus clinical manifestations. Prior to the rash, the patient was receiving the same antihypertensive therapy, and the added drugs were methylprednisolone and hydroxychloroquine. Methylprednisolone was replaced by prednisolone, and hydroxychloroquine was immediately discontinued. Doctors identified hydroxychloroquine as a causal factor of TEN because it was the only new molecule the patient had been taking for the past 2 weeks.
The case of poisoning with a mixture of drugs
In the journal Emergency Medicine, the DrugCard platform found an article which describes a clinical case of severe poisoning with a mixture of drugs with mostly cardiotoxic effects. The patient with suicidal intentions took 250 tablets of nifedipine (approximately 2,500 mg) and 25 tablets of gidazepam (500 mg). The dose of drugs taken was many times the potentially lethal dose. The article describes in detail the stages of medical care for the patient and indicates the consequences of overdose. After 26 days in the intensive care unit, the patient was transferred to the treatment unit in a stable condition and without neurological deficits. Severe poisoning by calcium channel blockers is quite rare among other drug intoxications. The authors of the article emphasize that in this case there was a mix of medications. The discussion focuses primarily on the pathological effects of nifedipine, as the effect of gidazepam was not decisive in the clinical symptoms of overdose.
A case of symptomatic hyponatremia
In the medical journal Emergency Medicine, the DrugCard platform also found a case of symptomatic hyponatremia. The elderly patient had complaints of headaches and elevated blood pressure to 180/100 mm Hg. After the infusion of furosemide and polarizing mixture (5% glucose + potassium chloride + magnesium sulfate) a deterioration suddenly appeared. In addition to consciousness depression and the development of neurological symptoms, the blood sodium level decreased to 102.8 mmol/l, and chlorine to 67 mmol/l. The authors claim that the cause of hyponatremia was most likely the infusion of 5% glucose and furosemide. Elderly people find it difficult to tolerate changes in blood osmolarity. With age, the regulatory interactions between osmolarity, ADH secretion and sensitivity of distal nephron aquaporin channels to ADH are disrupted. Osmotic diuretics may also decrease blood sodium levels due to the mobilization of free fluid from the intracellular to the intravascular space.
Regulatory requirements for literature drug safety cases reporting
According to the validity criteria, all these mentioned literature cases are valid because all 4 minimum criteria are present:
- patient data (sex, age, diagnosis);
- adverse reactions manifestations;
- suspected drugs (active substance, dosage);
- reporter (medical institution, authors of the article).
In case the article doesn’t specify the drug trade name or manufacturer, the active substance determines the reporting responsibilities. Thus, such articles clearly show the need for MAHs to conduct local medical literature monitoring to identify relevant safety cases. With DrugCard automated pharmacovigilance platform, you won’t spend valuable time searching for publications that mention your drugs. DrugCard will find them by keywords and inform you about the availability of articles that need evaluation by pharmacovigilance specialists.