Coming full circle in pharmacovigilance: communicating safety information to patients through patient package inserts.

Optimal drug therapy requires that the patient should be informed adequately, unequivocally and in timely fashion. Patient package inserts (PPIs) have an important facilitating role to play in this respect. Patients' confidence in the benefit of a drug treatment and their fear of its side effects are strong determinants of their adherence to that treatment. Yet, the European PPI format does not allow a discussion of the treatment's benefits, which results in an unbalanced focus on side effects. This serious shortcoming may significantly interfere with a patient's compliance. In addition, prescribers are often unaware of the content of the PPI of the products they are prescribing. To rectify this situation, the development is proposed of annotated PPIs providing the scientific background to the PPI message. In conclusion, European PPIs need to be improved. The patient should be informed of the expected benefit of a drug treatment, its likelihood and the expected time course of the effect, and not only of side effects and interactions, which constitutes the present focus. Moreover, prescribers need to be informed about the content of the PPIs for the medicines they prescribe.

Why there is a need for pharmacovigilance.

Not everything is known about a medicine when it receives its licence for marketing. The merits of a new drug, balancing its beneficial and its untoward effects, become only established after sufficient experience has been gained from its use in real practice. Part of the reason for this is that our extensive phase III clinical trials fail to detect some side-effects. Why is this so? Three groups of reasons may be envisaged, namely (1) our trials lack the power to detect rare side-effects; (2) some side-effects do not occur in the context of clinical trials; (3) some side-effects, though common enough, fully or partly escape detection due to lack of suitable detection techniques. The following presents a closer look at these three mechanisms.

Post-marketing cohort study comparing the safety and efficacy of flunarizine and propranolol in the prophylaxis of migraine.

A comparative post-marketing surveillance study of the safety and efficacy of flunarizine and propranolol in the treatment of migraine was carried out. General practitioners in Belgium and the Netherlands each recruited patients for whom they would prescribe one of the study medications in the normal course of their treatment and recorded all medical events on follow-up forms for up to 8 months. A total of 1601 migraine patients were enrolled; 838 in the flunarizine cohort and 763 in the propranolol cohort. Propranolol was somewhat better than flunarizine in reducing the severity of migraine attacks, although this may have been due to a selection bias. Discontinuations of therapy due to events considered likely to be treatment-related were mostly due to the recognized side effects of the two drugs. As regards the occurrence of depressions, a total of 58 patients had depressive events, 34 in the flunarizine cohort and 24 in the propranolol cohort. Whereas migraine itself appears to be associated with an increased risk of depression, the number of previous migraine treatments was shown to be an additional risk factor for the development of depression in patients receiving flunarizine as was a history of depression. Overall, there was no appreciable difference in the risk/benefit ratio between flunarizine and propranolol.

Postmarketing study of the use of flunarizine in vestibular vertigo and in migraine.

OBJECTIVE: This international postmarketing observational study of flunarizine was designed to evaluate, in routine clinical practice, the risk/benefit ratio of flunarizine in its approved indications, namely prophylaxis of migraine and treatment of vertigo. Comparator drugs were propranolol in migraine and betahistine in vertigo. The study was carried out by 498 general practitioners in Belgium, The Netherlands and Germany, whose participation had been requested by mail. In total 3186 patients were entered: 1601 in the two migraine cohorts and 1585 in the two vertigo cohorts. RESULTS: In the migraine study, treatment results with propranolol tended to be somewhat better than those with flunarizine, but a selection bias cannot be excluded. There was no clear difference regarding efficacy between flunarizine and betahistine in the vertigo study. The safety evaluation focused on extrapyramidal symptoms (EPS) and depression. Overall, EPS were noted in only four patients, two in the vertigo-betahistine and two in the migraine-flunarizine cohort. A total of 70 patients developed depressive symptoms (34 in the flunarizine and 24 in the propranolol migraine cohorts, but only 7 in the flunarizine and 5 in the betahistine vertigo cohorts). Patients with migraine were clearly more prone to depression than patients with vertigo, regardless of their treatment. Additional risk factors for depression were a history of depression, and, in the migraine flunarizine cohort, a high number of previous migraine treatments.

Risk of selected serious cardiac events among new users of antihistamines.

This retrospective cohort study examined the risk of selected serious cardiac events in new users of either astemizole or sedating antihistamines identified from the COMPASS Ohio Medicaid population of approximately 1 million active lives per year (1986-1992). (COMPASS is an automated claims database.) There were 15,585 patients in the astemizole group and 30,105 in the sedating antihistamines group. Reports of ventricular arrhythmia or sudden death occurring within 30 days of the first antihistamine claim were identified from Medicaid claims. Medical records were obtained and reviewed by a clinician for validity of diagnoses. Records for patients without a full 30 days of follow-up were sought in the National Death Index. Death certificates were obtained for all patients who died within 30 days of the first antihistamine claim. Of 53 cases identified, 6 were in the astemizole group and 47 in the sedating antihistamines group. The relative risk for all selected cardiac events among astemizole users compared with sedating antihistamine users was 0.25 (95% confidence interval: 0.11 to 0.58), and this estimate did not change substantially when adjusted for age; sex; race; recent history of cardiovascular disease, arrhythmias, asthma/pulmonary disease, or malignant neoplasms; or concomitant prescription of other drugs. This study provided no evidence that astemizole users are at increased risk for cardiac events in the first month of use when compared with users of sedating antihistamines.

Reproducibility of QTc-measurements in healty volunteers.

To assess the potential time-dependency and the reproducibility of the QTc-interval, ECG's from 84 healthy volunteers, recorded between 8 a.m. and 4 p.m., were analyzed. QT and RR intervals of all ECG's were measured by the same observer and Bazet's formula was used to correct QT intervals. The QTc-value showed a diurnal rhythm; its duration being minimal at 10 a.m., after which is gradually returned to the 8 a.m. value by 4 p.m. The 10 and 12 a.m. QTc's were statistically significantly shorter than the 8 a.m. QTc-interval (p < 0.05). There was not circannual rhythm. There was marked QTc-variability within one day, irrespective of the time at which the ECG had been obtained. Similar QTc-variability was also observed after longer intervals (week(s) or month(s)).

QTc-measurements: a case-control study on serum electrolytes.

This is a report on a prospective case-control study, in which a group of patients with an electrocardiographic diagnosis of QTc-prolongation (cases) was compared with a group of patients with a normal QTc (controls) for the presence of potential causative factors. Twelve cases and twelve carefully-matched controls were entered during a 1-year recruitment period. Ventricular arrhythmias were more frequent amongst the cases than amongst the controls (7/12 the cases, only 2/12 controls). Blood was sampled around the time of the ECG-recording in all patients. Forearm exercise (pumping) to increase venous blood pooling was prohibited before this blood sampling. The serum cation levels (potassium, calcium, magnesium) were determined in one central laboratory. Serum potassium levels were inversely correlated with the QTc-interval. Such a correlation was not found for the other two cations, although calcium levels also tended to be lower in patients with a long QTc. The findings, in addition, suggest that serum potassium values in the lower normal range (i.e. < 4 meq/l) might predispose to the development of ventricular arrhythmias. In view of these results, the diagnostic work-up of a patient with a long QTc is incomplete without a serum--K+, and possibly serum--Ca2+, assessment.

Levamisole, the story and the lessons.

The history of the use of levamisole in man is summarized, from its start as an anthelmintic in the early sixties, through its world-wide recognition as an immunotropic agent especially in the seventies and early eighties, and its return to clinical prominence in 1989-90 as an effective adjuvant treatment for operable colon cancer. The knowledge accumulated from experimental tumour models and from clinical use in various types of cancer, supplemented with the recent evidence obtained from large-scale controlled trials in resectable colon cancer is reviewed. It is speculated that we may not have seen the end of levamisole story yet; also, the role of serendipidity in drug research is emphasized.

The role of the gut in migraine: the oral 51-Cr EDTA test in recurrent abdominal pain.

Sixteen children with recurrent abdominal pain (or: "recurrent syndrome"), regarded as migraine equivalent in childhood, were submitted to the 51-Cr EDTA gut permeability test. The results were compared with those obtained in 10 healthy young adults and in 11 control children. The gut permeability in the recurrent syndrome was significantly higher than in healthy adults and control children (p less than 0.0006): The following results were obtained: 4.83 +/- 0.40 (mean +/- SEM) in the children with recurrent abdominal pain, and 2.35 +/- 0.24 2.51 +/- 0.21 in the healthy young adults and control children, respectively. The implications of these findings as far as migraine is concerned, are discussed.

Prophylactic and curative treatment of migraine with calcium antagonists.

The present review discusses the available clinical information dealing with the treatment of migraine with calcium entry blocking agents. The data on prophylactic therapy are limited to 3 compounds, of which flunarizine is the most extensively studied and the only substance whose activity is well established. Clinical experience with these agents in the acute treatment of migraine attacks is still very limited.

Aromatase inhibition by R 76713: experimental and clinical pharmacology.

R 76713 is a new non-steroidal compound which inhibits aromatase in vitro and in vivo with a potency of at least 1000-fold that of aminoglutethimide. In male cynomolgus monkeys peripheral conversion of labeled androstenedione to estrone is decreased by 85%, 4-5 h after a single intravenous dose of 0.003 mg/kg of R 76713, without altering steroid metabolic clearance rates. In rats fed a sodium-depleted diet for 3 weeks, plasma levels of aldosterone and plasma renin activity remain unchanged 2 h after a single oral dose of up to 20 mg/kg of R 76713. This confirms previous data on the selectivity of R 76713 for aromatase inhibition as compared to inhibition of other enzymes involved in steroid biosynthesis. In male volunteers, a single oral dose of 5 or 10 mg of R 76713 lowers median plasma estradiol levels from 70 pM to the detection limit of the assay (30 pM) 4 and 8 h after intake, whereas no important changes are detected after placebo administration. In 15 premenopausal female volunteers receiving a single oral dose of 20 mg of R 76713, mean plasma estradiol levels decrease from 415 pM (before) to 179, 149 and 185 pM respectively 4, 8 and 24 h after intake whereas they remain above 380 pM after placebo (n = 7).

The sensorium of the migraineur.

The occurrence of perceptual disturbances in migraineurs, particularly during the headache-free interval, has been scrutinized rather rarely. This subject was studied via a mail survey in 134 patients presenting perceptual changes before or during their migraine attacks. The patients had to complete a 5-part questionnaire covering history, events before, during as well as after the attack, and the attack-free interval. Sensory alterations during the headache-free interval were not reported by 36.6% of the patients. Alterations of equilibrium and/or spatial orientation, mainly susceptibility to motion sickness, were present in 47.8%, increased sensitivity to cold or heat in 40.3%, intolerance of tight clothes or being touched in 34.3%, altered visual function in 32.8%, changes in olfactory acuity in 31.1%. These percentages show that these 5 types of interictal sensory disturbances may not be rare in migraineurs. The exact frequency of these symptoms and how they correlate with perictal phenomena, sex, age and disease characteristics has to be further studied.

Hepatic cytochrome P450-mediated oxidation function in migraine.

Hepatic cytochrome P450-dependent oxidation is deficient in 5% to 10% of the Caucasian population. A similar percentage seems to suffer from migraine. The hypothesis was tested that an oxidation deficiency possibly relevant to potential dietary triggers plays a role in the pathogenesis of migraine. In 37 migraine sufferers and 26 controls age- and sex-matched to 26 of these patients, debrisoquine hydroxylation following an oral dose of 10 mg was employed as a marker of oxidation status, determined by calculating the metabolic ratio (MR): urinary debrisoquine/urinary 4-hydroxydebrisoquine. MR was similarly distributed in migraineurs and controls. Three subjects in each group were poor metabolizers (MR greater than 30, versus normal range, 0.1-12). MR in patients did not depend on type of migraine (common versus classic), attack frequency, the presence of trigger factors, smoking or a history of adverse reactions or sensitivity to medicines.