Veterinary Pharmaceutical Dosage Forms: A Technical Note

  

    
Organ/system involved 
    
Adverse effects
  
  

    
Immune system
    
Anaphylaxis
  
  

    
Nervous system
    
Dizziness, Headache
  
  

    
Cardiac
    
Tachycardia, palpitation
  
  

    
Gastrointestinal
    
Nausea, dry mouth,    gastritis
  
  

    
Hepatobiliary
    
Abnormal hepatic function
  
  

    
Skin    and subcutaneous tissue
    
Rash, alopecia
  
  

    
General    disorders and administration site conditions
    
Fatigue, somnolence,    increased appetite
  

Table 1:  The adverse effects of oral loratadine (Summary of Product Characteristics for the reference drug Clarityn Allergy®, own modification).

According to current literature sources, loratadine is a very safe drug [3,4]. The most serious andfrequent adverse effects of loratadine include somnolence, tachycardia and headaches [5]. Furthermore, administration of the drug may cause sleep disorders, vertigo, cardiac arrhythmias, nausea, vomiting, diarrhoea or constipation, and vision disorders [4]. Allergic rash and a receding hairline were also reported [6]. Table 1 below lists the adverse effects contained in the Summary of Product Characteristics for the reference drug Claritine (Table 1).

In clinical trials in a paediatric population, in children aged 2 to 12, common adverse reactions reported in excess of placebo were: headache (2.7%), nervousness (2.3%), and fatigue (1%). In clinical trials involving adults and adolescents for a range of indications including allergic rhinitis and chronic idiopathic urticaria at the recommended dose of 10mg daily, adverse reactions with loratadine were reported in 2% of patients in excess of those treated with placebo. The most frequent adverse events reported in excess of placebo were: somnolence (1.2%), headache (0.6%), increased appetite (0.5%) and insomnia (0.1%). Other adverse reactions were reported very rarely during the post-marketing period (SmPC, Claritin, 2011).

Polish current pharmacovigilance system is based on EU legislation. As part of the pharmacovigilance system, the manufactures monitor spontaneous reporting i.e. adverse reaction reports submitted by healthcare professionals and patients or their guardians. The manufactures cooperate with the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products based in Warsaw, which is the central pharmacovigilance unit in Poland. The monitoring system is focused on the detection of new drug interactions and adverse reactions as well as groups of patients more prone to adverse reactions.

Aim of the Study

Analysis of the adverse events of oral loratadine marketed in Poland to detect new, as yet unknown adverse effects of loratadine and evaluates loratadine safety.

Material and Methods

We contacted all five manufactures marketing loratadine in Poland (Hasco-Lek S.A. Galena, US Pharmacia, Sandoz, MSD Polska) in last 6 years. Data concerning loratadine adverse reaction reports and sales volumes in Poland available in a passive spontaneous reporting system were analyzed, covering the period between January 2008 and December 2013.

Results

During the analysed period the manufacturers marketing loratadine in Poland received only five adverse event reports.

The first report involved an 82-year-old female patient who suffered a sudden rise in blood pressure up to 195/105 mmHg accompanied by tachycardia (pulse132/minute) following administration of one Loratan capsule. The patient was treated for chronic depression, ischaemic heart disease and arterial hypertension with: Coaxil, Doxepin, Amlozek, Effox long and Hydroxyzine syrup. Once the drug was withdrawn, the adverse effects did not reoccur.

The second patient was over 60-year old woman taking aspirin and dietary supplements (Bodymax, magnesium containing products). A rash on the trunk was observed after she had taken a single LoratanPro capsule (over the counter medication).

The third patient was a 39-year old woman chronically treated with several antipsychotic medications (Absenor 500, Chlorprotixen Zentiva 50mg, Sulpiryd 50 mg) for psychosis associated with schizophrenia. An exacerbation of allergic symptoms including swelling around the eyes, tearing, burning and redness of the skin was observed when she had taken a loratadine tablets.

The fourth patient was 28-year old man treated for allergic rhinitis with Buderhin (budesonide intranasal aerosol)and Loratadine Galena 10 mg tablets. The patient complained about drowsiness and vertigo, which disappeared after discontinuation of loratadine tablets.

The fifth patient was 61-year old diabetic woman chronically treated with insulin, Prestarium and Bisocard. Adisseminated erythematic rash on the trunk and extremities with itching was observed after she had taken a single loratadine tablet (Loratadyna Galena). Similar adverse reaction had been observed 2 months before, when she had taken a tablet of Claritine.

The Polish total loratadine market in period 2008-2013 was estimated at 3.2 to 5.3 million packs per year. About 26.7 million packs of loratadine containing products were sold in Poland in ³ year period analyzed.

Discussion

The adverse effects of loratadine are similar to other non-sedating antihistamines in general. In contrast to sedating antihistamines which the most common adverse effect is Central Nervous System (CNS) depression, non-sedating antihistamines generally cause little or no drowsiness. The most commonly reported adverse effects of standard loratadine dosage (10 mg/daily) were: headache (12%), somnolence (8%), fatigue (4%) and dry mouth (3%) [7]. Loratadine like most non-sedating antihistamines has little anti-muscarinic effect. That is why typical anti-muscarinic effects, such as dry mouth, thickened respiratory-tract secretions, blurred vision, urinary difficulty or retention, constipation, and increased gastric reflux are reported rarely. The other adverse effects include headache, psychomotor impairment and occasional gastrointestinal symptoms: nausea, vomiting, diarrhea and epigastric pain. Palpitations and arrhythmias although reported occasionally were a particular disadvantage of the astemizole and terfenadine, the non-sedating antihistamines. The hazardous ventricular arrhythmias led to important restrictions on their use but were not reported with loratadine, which has a broad therapeutic margin and does not prolong the QT interval [8]. Antihistamines sometimes cause rashes and other hypersensitivity reactions (including bronchospasm, angioedema, and anaphylaxis). Blood dyscrasia (agranulocytosis, leucopenia, haemolytic anaemia, and thrombocytopenia) although rare, have been reported. Jaundice has also been seen. Convulsions, sweating, myalgia, paraesthesias, extrapyramidal effects, tremor, sleep disturbances, depression, confusion, tinnitus, hypotension, and hair loss have been reported with the antihistamines [9].

According to FDA records, loratadine is characterized by very good clinical safety and adverse reaction reports are recorded approximately twice every 100,000 therapies [2]. Analyses of loratadine-containing medicinal products during their 6-year market presence on the Polish market prove their safety. Only five adverse reaction reports against a 26.7 million packs distributed(less than 1 adverse event per million) may, however, suggest low sensitivity of the existing polish pharmacovigilance system. According to FDA records, approximately 60 reports should be expected [2]. Similarly, the electronic drug safety RxISK database (https://www.rxisk.org/ Default.aspx) also including consumer reports, contains 2,685 reports where loratadine was the suspect drug covering 8,942 reactions, of which 1,868 do not specify the patient’s country. RxISK data base is based on 3.9 million reports submitted to the FDA’s MedWatch from 1^st January 2004 to 31^st March 2012, of which approximately a third of these reports come from outside the United State. This may result from a lack of awareness among medical professionals on the usefulness of any adverse drug related data, including known and common adverse reactions. The weakness of this paper is that it is based on passive adverse event reports and the cases were confounded and there was no dechallenge-rechallenge data available. Presented cases leave unanswered question regarding causality. The strength is of our study is a 6-year observation period of the entire Polish population.

Conclusion

No new adverse effect of loratadine was identified. Oral loratadine is a very safe medication rarely causing already known adverse effects. However, the existing spontaneous monitoring system of adverse effects in Poland is not sensitive enough and needs improvement.

References

1. Kay GG, Harris AG. Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation. Clin Exp Allergy. 1999; 29: 147-150.
2. FDA 2002, Claritin Marketing History.
3. Phan H, Moeller ML, Nahata MC. Treatment of allergic rhinitis in infants and children: efficacy and safety of second-generation antihistamines and the leukotriene receptor antagonist montelukast. Drugs. 2009; 69: 2541-2576.
4. Sweetman SC. Martindale: The Complete Drug Reference. London, Pharmaceutical Press. Electronic version, 2012.
5. Drug Bank. Loratadine. 2012.
6. MSD Clarityn Tablets. Summary of Product Characteristics last updated on the eMC. 2012.
7. Montvale NJ. Physicians' Desk Reference. 50th edn. Medical Economics Co. 1996.
8. Simons FE. H1-receptor antagonists. Comparative tolerability and safety. Drug Saf. 1994; 10: 350-380.
9. Horak F, Stübner UP. Comparative tolerability of second generation antihistamines. Drug Saf. 1999; 20: 385-401.