Phytopharmaceuticals, as other drugs, can cause undesirable side effects. There is a perception, especially in patients, that being "natural" they are safe and cause no unwanted effects; patients often fail to mention they are taking herbal medicines to doctors. Pelargonium does appear to be a well tolerated medicine but does have recognised adverse events associated with its therapeutic use, most notably of the gastrointestinal system. The public access site of the WHO, VigiAccess, of the global database of adverse drug reactions, VigiBase, lists over 1300 reports associated with Pelargonium sidoides. The majority of the reports originated in Asia and Europe
While often used interchangeably, the terms Adverse Drug Reaction, Adverse Event and Side Effect but have different meanings.
Adverse Drug Reaction (ADR) is a harmful or undesirable response to a medication that has been used at normal doses for prevention, diagnosis or treatment of a medical condition. All ADRs are adverse events.
Adverse Event (AE) is a broader term to describe any negative or unfavourable medical occurrence that happens to a patient during or after a medical intervention or use of a drug. This might include an ADR but can also include other unintended medical complications that have not been caused by the medication.
Side Effect is an older term that describes both negative and positive effects of a medication. It is not synonymous with ADR or AE. The side effects of some drugs are used for therapeutic benefit. For example anticholinergics for treating urinary incontinence, the anticholinergic (antimuscarinic) effect on sweat glands can used for patients with hyperhidrosis. The term is not recommended for use by the European Medicines Agency.
A Serious Adverse Drug Reaction or Serious Adverse Event is defined as one that results in one or more of the following:
- death
- is life-threatening
- requires in-patient hospitalisation or prolongation of existing hospitalisation
- persistent or significant disability/incapacity
- a congenital anomaly/birth defect
There is an adopted convention for reporting adverse drug reactions from very common (1 in 10/10% or more) through common, uncommon and rare to very rare (less than 1 in 10,000).
Common: from 1 in 10 to 1 in 100 (1% to 10%)
Uncommon: from 1 in 100 to 1 in 1,000 (0.1% to 1%)
Rare: from 1 in 1,000 to 1 in 10,000 (0.01% to 0.1%)
Very Rare: less than 1 in 10,000 (0.01% or less)
Common (1 in 10 to 1 in 100): None
Uncommon (1 in 100 to 1 in 1,000): Gastrointestinal complaints such as stomach pain, heartburn, nausea, vomiting, difficulty swallowing or diarrhoea
Rare (1 in 1,000 to 1 in 10,000): Mild bleeding from the gums or nose. Allergic reactions such as skin rash, itching of the skin and mucous membranes
Very Rare (less than1 in 10,000: Serious allergic reactions with swelling of the face, shortness of breath and decrease in blood pressure
Frequency not known: Hepatitis or other liver problems.
Safety data from Clinical Trials
One of the most comprehensive reviews of Pelargonium safety was published by Matthys et al (2013). The authors included 29 trials in the review, 19 of which were RCTs, the others being pharmacokinetic, post marketing surveillance, open label outcome studies. A total of 10,026 patients were included across all the studies, 8,005 patients were exposed to Pelargonium.
There were no serious adverse drug reactions (SADRs) and four serious adverse events (SAEs) which were not related to the medication. Adverse events were reported in between 1.4% and 51.5% of patients taking Pelargonium and 0.0% and 39.6% of patients receiving placebo. Adverse drug reactions (AEs with a causal relationship to the medicinal product) were analysed in 4,345 patients (2,478 treatment and 1,867 placebo). Risk differences were reported between treatment and placebo groups for gastrointestinal complaints with a risk difference 1.86% (3.63% vs 1.77%, p=0.002) and for hypersensitivity reactions 0.26% (0.36% vs 0.11%, p=0.036). There were no statistically significant differences on the other system groups. These observations were largely in line with the SmPC of Pelargonium, albeit with higher frequency.
The Cochrane review by Timmer et al (2013) analysed the adverse events. AEs were rarely reported but eight trials were included in the meta-analysis. AEs were slightly more common in the Pelargonium treatment group than placebo group (Risk ratio 1.11, 95% CI 0.69 to 1.79, p=0.02%).
Hepatotoxicity
A number of spontaneous reports of assumed liver disease related to Pelargonium submitted to the German Medical Association. Two publications by Teschke et al (2012) analysed the reports and concluded that despite the poor documentation causality was unlikely. Alternative diagnoses included viral hepatitis, acute pancreatitis and cholangitis, autoimmune liver diseases and pre-existing liver diseases including cirrhosis.
Additionally, the review of Matthys (2013) evaluated the trials that had examined liver enzymes and bilirubin. They demonstrated that the numbers of patients that had normal results at baseline and elevated after treatment was small and similar in both the treatment and placebo groups. Additionally, a higher proportion of patients had elevated levels at baseline which returned to normal after treatment. A similar observation was reported in a trial of Pelargonium in children with acute bronchitis by Kamin et al (2023).
A single case of fatal hepatotoxicity following Pelargonium treatment was reported as a conference abstract by Bonaiuti et al (2012) from Italy. The patient was a 46-year old male with multiple co-morbidities and poly-pharmacy but normal liver enzymes 15 days prior to receiving Pelargonium treatment for six days. The patient was admitted with severe asthma, tachycardia and raised liver enzymes. The patient died on the fourth day after admission with acute liver failure and respiratory distress. The causality assessment was defined as possible with relation to Pelargonium.
Teschke et al (2012) argue that only verified cases with proven causality should remain on the database. The authors suggest that suspected cases of herb induced liver injury (HILI) should be carefully peer reviewed and pre-existing liver disease excluded before including cases on the pharmacovigilance database. They concluded that there is currently no evidence of hepatotoxicity related to the use of Pelargonium. Currently the warning of hepatitis when taking Pelargonium remains on the SmPC and information leaflet of the licensed products but the frequency cannot be estimated from the available evidence.
A recent Pharmacovigilance Risk Assessment Committee (PRAC) report of the European Medicines Agency (EMA) recommended cases of hepatotoxicity should be closely monitored.
Hypersensitivity
Hypersensitivity reactions following ingestion of Pelargonium are recognised and rare; anaphylaxis is very rare. Most reactions are mild in the form of a rash, pruritis, urticaria, dermatitis, rhinitis and asthmatic symptoms. A smaller number of cases of anaphylaxis have been reported with circumoral and tongue oedema, dyspnoea and circulatory collapse.
de Boer et al (2007) reviewed 34 case reports submitted to the WHO international pharmacovigilance programme at the Uppsala Monitoring Centre (UMC) known as Vigibase. They reported that due to the description of the events and the timing in relation to drug ingestion that 15 of these cases were suggestive of a Type I hypersensitivity. Two patients required treatment for circulatory collapse.