It is a large, innocuous-looking, white tablet but controversy surrounds an anti-malarial drug which is taken every year by thousands of Irish people. The drug, Lariam, is widely prescribed for people travelling to areas in which there is resistance to older drug treatments for malaria.
But Lariam has been accused of bringing on fits, causing psychosis, and, according to one Irish man, it has ruined his life, leaving him unable to work for almost two years, and some days barely able to get out of bed.
There has been debate in the medical press for more than 10 years about Lariam's possible side-effects A number of people in the UK have issued proceedings against the manufacturers. They claim under consumer legislation, that the manufacturers, Roche, marketed a defective product failing to give adequate warning of the side-effects. Similar moves are being made in the US.
The difficulty when discussing the side-effects of Lariam is that you must weigh up the "acceptable" side effects against a potentially fatal disease such as malaria. Malaria is the world's most dangerous, insect-borne disease, and it kills an estimated 3 million people each year.
In Ireland, Lariam is marketed by Roche Pharmaceuticals. Its managing director, Mark Rodgers, says the danger of contracting malaria and "its attendant risks including death, are horrifying to contemplate against the relatively modest potential for developing side effects against anti-malarials, including Lariam". He says research has shown, that the side effects for Lariam, which is also known by the generic name mefloquine, are similar to those of the other drugs available. "Lariam has been identified by the World Health Organisation as one of the world's most essential medicines."
In January 1996, Rodgers sent a letter to doctors reminding them - in light of media attention on Lariam, "which referred to its safety profile, with particular emphasis on the incidence of neuropsychiatric effects" - of the contraindications of the drug. The letter explained that Lariam is an anti-malarial agent used in the treatment and prevention of malaria in those areas in which resistance to earlier, conventional, anti-malarial therapy exists.
The drug, he continued, should not be given to patients with kidney or liver problems, those with a history of or existing psychoses or epilepsy or those with a known hypersensitivity to Mefloquine or related compounds. "Patients should be informed that if they develop one of the following symptoms they should seek immediate medical advice," the letter said. The symptoms listed included psychological changes "such as depression, confusion, anxiety, hallucination, psychotic or paranoid reactions, sleep disorders, including abnormal dreaming, forgetfulness, abnormal thinking". The Irish Medicines Board (IMB) issued a similar reminder in its May 1996 newsletter.
An IMB spokesman told The Irish Times that Lariam was an extremely effective anti-malarial drug, particularly in places where the malarial parasite has developed resistance to older drugs. He said it had a "known toxicity profile" which was well documented in the patient information leaflet. "Doctors should explain to people that there are side-effects." Last year, the IMB had 14 adverse drug reaction reports concerning Lariam - these related to agitation, anxiety, depression (with one case involving suicidal thoughts), dizziness, emotional upset, psychotic reaction, sweating, tremor, weakness. In 1997 there were seven reports including amnesia, fatigue, headache, muscle spasm, nausea and psychotic reaction, 10 in 1996, 12 in 1995, none in 1994 and one in 1993.
The Tropical Medicine Bureau, run by Dr Graham Fry, sees up to 15,000 people who are travelling overseas each year. The bureau prescribes Mefloquine routinely to around 4,000 people. Asked about the drug, Dr Fry says the "good points must be balanced against the bad points". At its worst, malaria can kill within 24 hours, he says. And it can be contracted easily: "I lived in the Congo for four years and never had malaria, nor did any member of my family. But I've had a patient who was in Victoria Falls for 24 hours who came back and got the disease," he says.
"People are travelling to much more high risk areas than they did in the past. In the (West in the) late 20th century, people expect perfect health but they are travelling to areas where people expect to be sick and there are huge health risks." Dr Fry explains that once a mosquito carrying the malaria parasite bites you, the parasite travels from the area of the bite to the liver cells within an hour. In the liver the parasites multiply over a period of up to a month. They then break out of the liver cells into the red blood cells, still multiplying, and eventually shattering the cells. "Apart from the itch you get from the bite, there are no symptoms until the red blood cells are shattered and then there are typical flu symptoms," Dr Fry says. "We have no drugs that significantly treat the disease other than against the red blood cell stage. If we can keep the prophylactics (preventative drugs) at a high enough level, then they (those who have contracted the disease) will not suffer the symptoms. That's why we tell people to take them for four weeks after they come home."
There are four major options when taking malaria prophylaxis, recommended by the World Health Organisation - chloroquine, proguanil, mefloquine doxycycline (an antibiotic). Some of these are becoming less effective in certain areas because of the resistance of the parasite. Lariam is considered the most effective anti-malaria drug on the market according to Dr Fry.
"In the high risk-areas such as the sub-Sahara the wisdom is that chloroquine and proguanil give approximately 60 to 80 per cent protection while mefloquine and doxycycline 90 to 95 per cent in those areas," he explains.
He says he discusses the side-effects and protection of the drug in-depth with his patients. "The final decision has to be their own." Standard practice for the past few years is to give it two to three weeks before travelling, so if problems develop there is early warning.
"It is extremely difficult to get any assessment of what the side effects are. Maybe you have heard about the difficulties and after taking one you get the collywobbles and decide to stop. Is that a side effect? Or if a patient said they had difficulty sleeping on holidays, or had nightmares? We have only had one patient that I would regard as being a significant case. We think she had an underlying cardiac problem which was exacerbated by the use of mefloquine. That was about four years ago and she has settled down since. People who deal with tropical medicine meet regularly and this is one of the main topics discussed. However, we do not see these patients who have suffered such side effects. We do not know where they are going. I would not want to lessen it for anyone, I am just surprised we do not see more."
However, in July 1995 Dr Gordon Cooke, consultant physician at the Hospital for Tropical Diseases in London wrote a letter to the British Medical Journal to alert other doctors to the dangers of Lariam. Dr Cooke said that only rarely did a week pass that he was not informed "by at least one traveller of his or her personal experience of side effects of mefloquine (many of them severe) or of similar symptoms in a colleague or fellow traveller".
Last year, following an article in a British Sunday newspaper on Lariam, Dr Cooke wrote that a letter asking why so little had been done by the relevant advisory committee about the "extremely unpleasant side effects" from the use of Lariam. Dr Cooke has also said the drug continued to be widely recommended with many thousands of travellers adversely affected. "I have never recommended it, which has led to allegations from colleagues that I have been responsible for an avoidable incidence of morbidity. It is important to weigh the efficacy of a malaria-preventive agent against compliance and adverse side-effects, bearing in mind that no preventive strategy against malaria is anywhere near 100 per cent effective," Dr Cook wrote.
However, a number of his colleagues, writing in the Lancet medical journal recently, have reported a large increase last year in the number of cases of malaria imported into the UK. Part of the reason for this, they said, was a reduction in the use of mefloquine (Lariam). Citing four cases, they said "incorrect, misleading or inadequate" advice had been given by healthcare professionals concerning the drug. Media coverage, they said, had added to the confusion.
They said there were discrepancies among the published reports of side effects, but admitted that part of the problem was that previous trials had concentrated on male military personnel, rather than travellers in general. However, speaking about balancing the risks, the authors said the cases of malaria occurring over the period they studied "make it clear that some travellers are not getting balanced, clearly-presented information about anti-malaria drugs . . . It is important that travellers know the advantages and disadvantages of the prophylactic regimens available."