Hacker News Reader

Comment by dholowiski | Hacker News Reader

Side effects (http://en.wikipedia.org/wiki/Modafinil#Side_effects)

In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including TEN, DRESS syndrome, and Stevens-Johnson Syndrome (SJS). The long term safety and effectiveness of modafinil has not been determined.

Webmd:http://bit.ly/9dSAg6 Headache, nausea, nervousness, anxiety, dizziness, and difficulty sleeping may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Tell your doctor immediately if any of these rare but serious side effects occur: mental/mood changes (e.g., agitation, confusion, depression, abnormal thoughts, hallucinations). Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, fast/pounding/irregular heartbeat, signs of infection (e.g., fever, persistent sore throat).

View on HN

6 cases over a decade. That's pretty safe in my book. You also left out the part about acute toxicity. For acute doses, Modafinil is safer than caffeine.

The FDA is ridiculously risk-averse when it comes to approving drugs. For example, they recently rejected lorcaserin and qnexa, two anti-obesity drugs, over safety concerns. They also got sibutramine withdrawn from the US market. Even if these drugs have risks, the risks of obesity are likely much higher.

A lot of people are going to die from obesity that would have been saved if these drugs were approved. Of course, the media reports when approved drugs cause harm, not when rejected drugs don't save lives.

Pharmaceutical products in the US that have unexpected side-effects can cause their owner to be sued into oblivion, and even incredibly rare side effects are likely to manifest if a large population is taking them. (Also, the population at large does not understand statistics & probability.) Look at the history of Thalidomide, that's where a lot of precedents were set.

This puts certain categories of drugs (anything for pregnant women, nootropics for people without alzheimers, etc.) in the "too risky to bother" category.

If pharmaceutical companies were so worried about getting sued into oblivion, they wouldn't submit those drugs for FDA approval. Since if the FDA actually did approve the drugs, the companies would get sued into oblivion.

The FDA is covering their asses politically, just as much as the pharmaceutical companies are protecting themselves against potential litigation.

(Also, your comment as posted contradicts itself, I think you meant to say "the companies wouldn't get sued into oblivion.")

I think that last comment is over-calling things a bit. There are no studies supporting the conclusion that anti-obesity drugs save lives (this is not to say that they definitely don't, just that no one has proven it). Most of them cause weight loss of only 2 - 5kg anyway, compared to dietary/behavioural intervention alone.

On the other hand, surgery for obesity is dramatically effective and there is good evidence that it saves lives. It is strongly recommended in appropriate patients eventhough 1 - 2% of people die because of the operation.

Don't think the FDA is being risk averse, they just decided not to approve a modestly effective agent with an unclear safety profile.

Don't decide that the FDA is risk averse on that one example, but I hope you can see how, in general, the FDA has every incentive to be too cautious. If the FDA approves a drug and people die then there'll be political hell. If the FDA delays the approval of a medicine by a year and a few people die during that year who could have been saved pretty much no one will say anything, and even if they never approve a needed mediation then only if its for a disease with a well organized group of sufferers (think AIDS or breast cancer) will there be a political price. Its a testament to the altruism of the people who work at the FDA that they approve things at all, since the politics of the situation are so against them.

I've only seen one study researching whether the FDA is too risk adverse overall. If you look at the number of drugs denied approval to, you find that the FDA saves about 2,000 lives each year, which is really awesome. On the other hand if you look at drugs that are later approved but which are delayed in testing you find that the FDA causes between 5,000 and 20,000 excess deaths each year, which sort of sucks. All of this doesn't include the effects of making drug companies more careful about which drugs they try out, which really might go either way in its effect. Remember when looking at those number that there's a definite diminishing returns effect with each additional level of inspection saving less lives but costing the same amount.

Of course, this is only one study but its the only one I've seen. If anyone could point to more data I'd be quite grateful.

> All of this doesn't include the effects of making drug companies more careful about which drugs they try out, which really might go either way in its effect.

Let's not underestimate the magnitude of this effect... the FDA is the way it is for a reason. As incredibly and hair-pullingly frustrating as the approval process can be, it's necessary. I'd rather have an FDA that errs on the side of caution than one that relies on the good will and stringent standards of the pharma industry.

Not to disparage the drug companies too heavily- most of the people who work in the industry developing and testing drugs have their heads on straight, and would be in favor of doing things the right way even without the FDA looking over their shoulders... but companies are companies, and ensuring drug safety is not something that should be left up to profit-maximizing entities. The story about the scorpion and the frog comes to mind...

I think you believe I'm trying to get rid of the FDA here. I'm not, I just want it to approve new drugs more quickly. Generally I'm in favor of things like the late 80s/early 90s reform which reduced the gap in approval speed between the US and Europe * , or like HR.6270 (which never made it to vote) which would let terminally ill patients use drugs that haven't been proven safe yet. There's no reason to get rid of the FDA, its probably both better and politically easier to reform it.

*Europe generally approved drugs much more quickly than the US (well, United Kingdom, France, Spain, and Germany at least) and there wasn't any statistically significant difference in the number of bad drugs let through. People noticed that and hence the reforms in the early 90s. For instance, you could use propranolol to treat hypertnsion in most of Europe by '68, but not in the US until '78. That cost 10,000s of lives right there. Luckily the modern FDA is better - though it still needs improvement.

> Even if these drugs have risks, the risks of obesity are likely much higher.

"Likely", nice weasel word there. In fact, sibutramine was pulled after the SCOUT trial showed that the risks of obesity were not higher. The cardiovascular risks of the drug more than offset the decresae in risks from lower weight.

Lorcaserin was barely efficacious, and had a cancer signal.

Qnexa was very efficacious, but had even more serious side effects. One serious one-two punch is that it makes women much more fertile because of the hormonal effects of weight loss (in the clincial trial something like 20 women got pregnant despite double birth control protection), and at the same time contains topiramate, a Pregnancy Category C drug known to cause birth defects.

You'll get no argument from me that the FDA is very risk averse (and I think there are several drugs rejected this year that should have been approved, e.g. pirfenidone for IPF), but I think you're wrong that the FDA should have approved these obesity drugs. As you say, obesity is a big problem in the US, which means lots and lots of people are going to take any drugs once they're approved. Such drugs have to be incredibly safe or there will be lots of problems.

The next obesity drug to come up for FDA approval is Orexigen's Contrave, and we'll see what happens there.

Hey, do you want to know what the side effects of birth control pills are?

Nausea, loss of sexual function, mood swings, increased risk of stroke, pulmonary embolism, and heart attack.

Give me some Provigil any day.

Come to speak of it, interfering with birth control does happen to be a possible side effect of modafinil.

Those abbreviated fatal conditions are severe systemic drug reactions involving skin. They are mostly idiosyncratic - in other words, not really related to the total dose and not more likely with long term use. Some people are unlucky and get these reactions, presumably due to genetic/immunological factors. HIV infection and SLE are known to increase the risk of TEN and SJS.

These reactions are rare, which makes it difficult to precisely quantify the risk. Other drugs which are known to cause these reactions are NSAIDs like ibuprofen, which you can buy from a supermarket, and antibiotics like amoxycillin or bactrim, which doctors prescribe without being particularly concerned about the risk of potentially fatal skin reactions.

Reply on news.ycombinator.com