A new drug safety signal identified by the Uppsala Monitoring Centre (UMC), Sweden a WHO Collaborating Centre for international service and scientific research within the field of pharmacovigilance. This safety signal is identified from the VigiBase, a global drug safety database maintained by UMC on behalf of WHO and published in the WHO Pharmaceuticals newsletter (2020 No.3).
Lack of drug dose titration (Medication error) during treatment with clozapine
Clozapine is an atypical antipsychotic medicine used as second-line treatment for schizophrenia in patients who are resistant to other anti-psychotic drugs (typical anti-psychotic drugs which were shown ineffective).
Schizophrenia is a severe mental health illness which affects a person’s ability to think, feel and behave consciously and clearly. Around 21 million people are affected with this condition globally. This disorder can be developed in different ways. The signs are classified into positive and negative symptoms.
Positive symptoms: Hallucinations and delusions, typically experienced during psychosis, patients interpret the world differently by seeing things and hearing voices that are not there, often resulting in abnormal behaviour and disorganized speech.
Negative Symptoms: These include the behaviors which result in a loss for the individual like self-neglect, apathy, social withdrawal, and loss of motivation.
Clozapine is a multireceptorial drug, which acts on 5-HT1A receptor as partial agonist by binding to and inhibiting dopamine D1 to D5 and serotonin receptors. Clozapine binds more strongly to dopamine D4 than to the other dopamine receptors, which explains its effect on the negative symptoms. The likelihood of developing extra-pyramidal side effects (a common adverse drug reactions for anti-psychotic class of medicines) is less with clozapine use when compared to other anti-psychotic medicines (Hence, the name given as atypical anti-psychotic for clozapine).
Clozapine Safety Profile (Risk of agranulocytosis):
The serious adverse drug reaction agranulocytosis (lowering of white blood cell count) associated with the clozapine had identified during the year 1975 (two decades after the drug launch date-1956). In Finland, 16 cases of agranulocytosis (including 8 fatal cases) were identified due to clozapine use which led to the withdrawal of drug from Finland and from some of the European countries. Other possible adverse drug reactions include myocarditis and metabolic side effects, higher risk of developing diabetes, due to the clozapine’s inhibitory action on the M3 receptor. Owing to these safety concerns, clozapine use is restricted to schizophrenic patients who are resistant or intolerant to other antipsychotic class of medications.
Importance of dose-titration during clozapine use:
The dose of clozapine plays a major role in terms of therapeutic beneficial effect and dose related adverse drug reactions (in overdose instances). The recommended dose for clozapine is 300 mg per day but doses up to 900 mg are generally acceptable, if required.
Significant safety concerns associated with therapeutic and higher doses of clozapine included-“higher risk of developing cardiac arrest, orthostatic hypotension, bradycardia, seizures, and syncope” (Dose dependent adverse drug reactions). Hence, it is important to consider the dose titration during treatment with clozapine. In the titration process, the patient is initially given a low dose which is then slowly titrated to higher dose. The starting dose administered to patient is 12.5 mg once or twice the first day, then dose is slowly titrated (increased) to 25 mg once or twice a day during the second day under close monitoring.
Dose Toleration: If the patient tolerates the dose, it can be increased successively until a safe and optimal therapeutic beneficial effect is achieved, which generally takes two to three weeks. When the maximum daily dose has been achieved, it should be divided to prevent undesirable adverse effects.
A slow dose titration is important during the below two situations to prevent the dose-dependent serious adverse drug reactions:
- Initial administration at the beginning time of treatment
- Re-introduction after the treatment interruption (omission of clozapine administration) which lasts for more than 48 hours
Safety Labeling Instructions for drug dose Titration:
The requirement of drug dose titration is specified in the product information documents of clozapine.
The summary of product characteristics (SmPC) for clozapine states that if the patient has stopped taking the drug for more than two consecutive days, “treatment should be re-initiated with 12.5 mg given once or twice on the first day”. A faster dose titration up to the optimal therapeutic level is acceptable if the dose is well-tolerated by the patient.
Signal Detection-Identification of Case Reports of ‘Lack of drug dose titration’ (Medication error) with clozapine use:
As part of routine signal detection process, Uppsala Monitoring Center (UMC) at Sweden performs periodic analysis of data present in the VigiBase (a WHO’s global drug safety database for individual case safety reports). During the process of screening for medication errors in the VigiBase, UMC identified a series of case reports describing “lack of dose titration when re-starting clozapine”.
Lack of performing dose titration during initial treatment and during re-introduction of clozapine is a treatment non-compliance which implies the failure to administer drug properly which is not in accordance with the drug usage instructions and conditions specified in the product information document-This comes under “product administration error” category.
As of October 2019, total 45 case reports were identified in VigiBase with the preferred term- “drug dose titration not performed” in relation to clozapine. These reports originated from the countries like Australia, the United States, the United Kingdom, and Ireland since 2015 reported by both health care professionals and patients/consumers. There was a slight increase in the number of reports with this medication error being submitted every year (Increased frequency- A new aspect of this safety finding).
These case reports commonly describe that the clozapine was stopped for some reasons and re‑administered after more than two days with the last intake dose without the knowledge and awareness of performing dose titration.
UMC highlighted three of the 45 case reports below:
“A 27-year old male had not taken his antipsychotic drug for one week because he had been on vacation. When he came back, he took his usual dose of 300 mg. Following the overdose, the patient became drowsy and altered behaviour and was admitted to hospital.”
“36-year old patient that has been taking the drug for more than 15 years forgot to pick up the prescription and therefore didn’t take the drug for three days. When he then took the drug again, he continued his normal dose and experienced sedation due to this overdose”
“A male patient stopped taking clozapine for eight days due to a bug he was suffering from. When he then re-started the treatment, he started with 100 mg which lead to mild tachycardia.”
The treatment compliance can be enhanced by emphasizing the importance of “re-titration of doses during re‑introduction of clozapine after a gap of more than two days” in the product information documents- (package information leaflets).