A few notes on the practical use of the DIPS

Question 1
The following are considered credible for this purpose:
- prospective studies showing clear evidence supporting the interaction, or
- case reports giving evidence to support the interaction, including cases in which applying the DIPS produces a result of possible or higher.

Question 2
The lists of enzyme inducers and inhibitors should be carefully pondered, since in vitro evidence does not always apply to in vivo conditions in straightforward manner.

Question 3
This calls for robust knowledge on the pharmacodynamic and pharmacokynetic characteristics of the object drug. In particular, medicines whose pharmacodynamics is affected by multiple factors may lead to false positive assessment outcomes. In the case of warfarin, for instance, the influence of dietary factors (vitamin K content) can easily be underestimated or altogether overlooked.

Question 4
The time lapse necessary for maximum inhibition to occur can be estimated from the half-life of the precipitant drug, whereas the half-life of the object drug will allow for the time of maximum change of the object drug to be estimated.

Question 5
These data are often unavailable in that both precipitant and object drug are often discontinued when a suspicion of interaction is raised. Neither can the dechallenge effect be evaluated if the doses of both drugs are changed.

Question 6
In those rare cases, usually due to unintentional rechallenge, that these data are available, the robustness of the causal relation obtained ends up being greatly reinforced.

Question 7
In this context, one of the most important limitations to causality assessment is insufficiently exploring alternative explanations for the observed reaction, other than a drug interaction.

Question 8
The answer to this question will often be “Non applicable”, since pharmacodynamic interactions do not usually entail changes in the concentrations of the object drug.

Question 9
Changes in physiological (laboratory) parameters may typically be objective evidence of a drug interaction.

Question 10
In those rare cases in which a dose-response relation can be established, the causality nexus is strongly reinforced.

The DIPS may well have significant limitations such as its as yet relatively limited use, the need for data that are often unavailable, as well as the need for relatively in-depth knowledge on both the implicated medicines. This scale however, shows great potential to become an indispensable tool for the evaluation of suspected drug interactions from an individual, case-by-case perspective.

Bibliografia selecionada

- Horn JR, Hansten P, Chan L-N. Proposal for a new tool to evaluate drug interaction cases. Annals Pharmacotherap 2007;41:674-80.

- Naranjo CA, Busto U, Seller EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

Pharmacovigilance: the Centre Regional Pharmacovigilance Unit, AIBILI, and the future

1. As the National Pharmacovigilance System Centre Regional Unit resumes its activity a new cycle is begun which aims for the development, validation and adaptation of methods to detect adverse events associated with drug exposure.

2. All the scientific output and experience gained during its initial four years (2000-2004) indicate and make it a necessity that regional units such as this should be on the way to becoming pharmacoepidemiological research hotbeds able to bring together and potentiate the know-how of health science university hubs such as Coimbra’s.

3. Spontaneous ADR reporting should be promoted on a continuing basis, provided qualitative and quantitative research and analysis is conducted accordingly.

4. It is anticipated that the paradigm for models of drug funding and co-payment is changing in such a way that post-marketing safety evaluation will take on a crucial role in gauging effectiveness. New needs to assess the impact of the use of medicines in contexts like the above make up for additional working opportunities for regional pharmacovigilance units.

5. The contracting model established between the regulatory authority (INFARMED) and the regional unit is in practice a form of service outsourcing. Its flexibility may be further explored to expand the national pharmacovigilance system into a much needed nation-wide pharmacoepidemiological network.

6. Teaching and post-graduate institutions, especially medical and pharmaceutical schools, can find in the regional unit an additional resource to help them fulfil their missions. Moreover they are thus able to integrate teaching, service and research under the same roof.

7. Health professionals working in this Region, thanks to their input through ADR reporting, are indispensable partners in our final and common goal: to optimise patient safety.

Finally, health policy decision-making, namely in what concerns the medicinal product environment, should bear in mind that pharmacovigilance is a structural pillar of sustainability for health systems.

Francisco Batel Marques
PharmD.
Professor, Coimbra University School of Pharmacy.
Coordinator, National Pharmacovigilance System Centre Regional Unit, AIBILI

There have been reports of cases of stress fractures of the proximal portion of the femoral diaphysis in patients submitted to long term treatment (18 months to 10 years) with alendronic acid.

The European Pharmacovigilance Working Party (PhVWP) has evaluated all data available on biphosphonates and risk of atypical stress fractures, including data from the published literature, pre-clinical studies, clinical trials, and post-marketing reports. It has been concluded that the available data support an association between atypical stress fractures and the long term use of alendronic acid. However, these data do not suggest that there is evidence of an increased incidence of atypical stress fractures with other biphosphonates. It is unclear whether this lack of evidence for other biphosphonates is due to limited use, to limited long-term data, or to a specific effect of the active substance, alendronic acid. The intense bone regeneration suppression mechanism involved may well be relevant for all biphosphonates, and a possible class effect cannot be excluded.

The SPCs and Information Leaflets are going to be altered in order to include information on the above risk.

Margarida Guimarães

Patients with schizophrenia or other psychiatric illnesses have an increased risk of comorbid physical conditions, including diabetes, complications of diabetes, and cardiovascular disease. The use of antipsychotic medicines (including second generation drugs such as olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole) can trigger or worsen these metabolic changes, which should therefore be carefully monitored.
The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes (American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity) reflects a joint statement by a group of specialist physicians involved in the treatment of psychiatric diseases, obesity and diabetes. It aims to make it clear which are the best procedures to follow in order to minimise the risk of metabolic changes caused by therapy with second generation antipsychotics (SGAs).

Monitoring schedule proposed by the guideline

Psychiatrists should not hesitate to refer the patient. On the other hand, nutrition and physical activity counselling should be provided for all patients who are overweight or obese, particularly if they are starting treatment with an SGA that is associated with significant weight gain. Referral to a health care professional or programme with expertise in weight management may also be appropriate.

If a patient gains ≥5% of his or her initial weight at any time during therapy, one should consider switching the SGA. In such a situation, the panel recommends cross-titration; abrupt discontinuation should generally be avoided.

For people who develop worsening glycaemia or dyslipidaemia while on antipsychotic therapy, the panel recommends considering switching to an SGA that has not been associated with significant weight gain or diabetes.

+ = increased effect; − = no effect; D = discrepant data
* more recent drugs with limited long-term data

All patients with diabetes should be referred to a recognised diabetes self-management education program, if available. Referral to a clinician experienced in treating people with diabetes is recommended. Although goals need to be individualised, blood pressure, lipid, and glycaemic goals for people with diabetes apply equally to those who also have psychiatric disorders.

Sibutramine
• metabolised by cytochrome P450 3A4

• Risk of increased dose-dependent adverse effects [cytochrome inhibition] with:
amiodarone, diltiazem, verapamil
macrolides (except spiramycin)
azole antifungals
certain antiretrovirals
grapefruit juice

• Risk of serotoninergic syndrome [summative effect]
MAO inhibitors in general, including the antibiotic linezolide
serotonin and noradrenalin reuptake inhibitor antidepressants
certain opioids (v.g., pethidine and tramadol)
lithium
triptans and dihydroergotamine
buspirone

• Risk of hypertension
corticoids, NSAIDs [summative effect]
venlafaxine, duloxetine, bupropion, nasal decongestants, triptans, MAO inhibitors, epoetins, levothyroxine,...
chronic alcohol consumption

• Risk of tachycardia
alpha and beta-agonists
levothyroxine, ...

• Risk of haemorrhage [summative effect]
antiplatelet agents, warfarin, ...

• Risk of decreased effect of antiglaucoma drugs [increased intraocular pressure]

Orlistat
• Little absorbed, eliminated fecally essentially unchanged

Risk of
• pregnancy with oral contraceptives [in case of major diarrhoea]

• vitamins ADEK deficiency [lipid-soluble vitamins]

• haemorrhage with vitamin K antagonists

• reduced effect of antiarrhythmics [decreased absorption]

The following may counter the weight loss effect:
• insulin (antidiabetic sulphonamides and glitazones)

• neuroleptics

• certain antidepressants

• certain antiepileptics (v.g., sodium valproate, gabapentin, pregabalin, levetiracetam, vigabatrin)

• piracetam

• certain anti-H1 antihistamines (v.g., cyproheptadine, pizotifen, ketotifen, phenothiazines)

• corticoids, danazol, raloxifen, tibolone, progesterone, ciproterone, megestrol

• methysergide; cyclosporin;...

Based on: la revue Prescrire

The Dutch medical device regulatory authority and the MA holder of the medicinal product Piky (available in Portugal) have made it known to INFARMED that, in several European countries, there have been some cases of serious hand and head burns related to the use of topical solutions for the prevention and treatment of human pediculosis. These products contain dimethicone (4%) and cyclomethicone (96%). When in contact with these products hair may be flammable. It is therefore recommended that after these solutions are applied hair should be kept away from sources of ignition, such as cigarettes, matches, lighters, or candles.