A ReLACSing Blog #20: Which Iron Infusion Should I Choose for Restless Legs?
Widely considered one of the first-line medical interventions for the treatment of restless legs syndrome (RLS), it is somewhat iron-ic that iron infusion is generally not covered by insurance strictly for RLS (OK, I promise only one or two more iron puns). However, those with bothersome symptoms of RLS and low or low-normal iron levels should not be deterred. Researchers now strongly believe low iron and/or poor iron metabolism inside the brain is a leading mechanism that creates the condition involving the irresistible urge to move the legs at night. For more than two decades now, iron supplementation–either by mouth or through an IV–has been shown to help improve the condition in a slight majority of patients with RLS. Here I discuss the forms of IV iron from my vantage point, also taking account of the unfortunate state of iron infusion in the insurance-based medical system.
Unless there is a need for rapid correction of low iron levels, most patients should first try iron supplements taken by mouth. Insurance also loves this treatment because supplements are almost always paid for solely by the patient. Iron supplements, however, have significant limitations. First, iron is often poorly tolerated as it could cause a stomachache or lead to constipation, thereby causing patients to stop the supplements. Second, if tolerated well, in certain situations, the iron is not absorbed by the gut well enough to budge the iron levels in the body. This may also be how the iron levels became low in the first place as well. Very little iron was getting in from food to maintain solid iron levels in the body. Giving more iron may not necessarily change that. Third, even if iron is absorbed optimally, the body has a natural mechanism for slowing down iron absorption in the gut once the body is happy and satisfied with how much iron it has. The iron levels at which the body is satisfied, may still be too low for the brain in those with RLS. If you can somehow get those body levels much higher than the status quo, then maybe it’s enough to offset the condition in which levels are too low for the brain.
Enter modern medicine and the thing called the intravenous catheter! Let’s say you can have a line placed in your forearm and get 6 months of iron supplements directly into your bloodstream in a matter of an hour! Well, that’s the idea behind iron infusions. There are no stomachaches, no constipation, no black-colored stool, and no bowels to be the gatekeeper from those wonderfully high iron levels. Great, you have decided (along with your licensed medical professional, of course) to get an iron infusion. There are several available in the US. Let’s assess the most common six of them here.
The first two are ones I do not recommend, unless you cannot get any of the big four I do recommend. A mediocre iron infusion is generally better than no iron infusion. Iron sucrose (Venofer®) and ferric gluconate (Ferrlecit®) are common, older, cheaper forms of IV iron. These, however, come in a molecule with relatively poor iron binding and can cause the release of “free iron” into the bloodstream. In other words, too much of these can cause a lot of that metal to be floating around freely and create unwanted side effects. Thus, there are limits on how much can be given at once, and have to be given in multiple infusions, often 5-6 trips to the infusion center with only 100-200 mg per infusion. The magic number for IV iron seems to be 1000 mg to create a robust response with RLS symptoms so you can do the math here. For gluconate, the average wholesale price may be $8 per 12.5 mg or $640 for 1000 mg. For sucrose, it may be $9 per 20 mg or $450 for 1000 mg. However, if you factor in the additional cost of several trips to the infusion center, these actually may be more expensive out-of-pocket than the more expensive formulations. What are the infusion center costs? Given the artificially inflated charges and lack of transparency by hospitals and medical centers, it’s anyone’s guess and varies from center to center and insurer to insurer. One has to guess the infusion fees to be equal or greater than these drug costs.
In addition to the hassles of multiple infusions and potential increased costs, these two seem to have poor H-ferritin binding, which may explain why these are additionally less effective for RLS. Those who get ferritin levels checked regularly for RLS may recognize the term. H-ferritin is a type of ferritin, or protein that is found in the blood that transports iron, and the H-ferritin is particularly adept at carrying iron into the brain compared to other ferritins. Some clinical studies including this one on iron sucrose have not shown the benefit to RLS compared to the stronger formulations of iron.
Of the ones I do recommend, low molecular weight iron dextran (INFeD®) is #1. It can be given safely over an hour at 1000 mg, and it is the least expensive ($19 for 50 mg or $380 for 1000 mg) of the stronger formulations of iron. This may be most cost-effective if paying out-of-pocket as it involves one infusion center excursion. There are some studies in RLS showing effectiveness, but this formulation has been commonly used over the years so RLS experts are very confident it works well. I had practiced at three academic medical centers at which this formulation was available, and I had a lot of positive experience with it. I then chose it to be the infusion formulation when setting up iron infusions for RLS at a fourth academic center. Two of the downsides of iron dextran are the occasional nationwide supply shortage and some infusion centers doing the infusion over a grueling four-hour period. This lengthened infusion time is due to the third downside: there is a stigma against iron dextran causing infusion reactions. A much older form of iron dextran, a high molecular weight form, which was taken off the market a decade ago, was known rarely to cause serious reactions in the past. This experience led to low molecular weight iron dextran saddled with a stigma that it too causes serious infusion reactions, even though there has been no evidence of this. Minor infusion side effects occur infrequently and serious reactions are extremely rare. In the US, a test dose of 25 mg is still required and the patient must wait 15 minutes before getting the rest of the infusion, sometimes over a very long infusion time of four hours due to the unfounded fears.
2. Ferumoxytol (Feraheme®) is #2 on my list, though I have infrequently had patients with access to this agent. If given at 1020 mg over no more than 20-30 minutes, this can be quite cost effective as well, particularly if one has at least partial insurance coverage. Many centers, however, still administer it over two infusions of 510 mg each, for which it was originally FDA approved. There are few side effects from it including minimal risk of hypophosphatemia (see below) and can be given over this short period without release of free iron into the bloodstream. The drug cost is ($1000 for 510 mg or $2000 for 1020 mg).
3. Ferric derisomaltose (Monoferric®): this is the newest agent, which is designed to be given in 1000 mg over one infusion in 20 minutes. It is the most expensive product (~$3000 for 1000 mg) and may not be covered by insurers unless several of the agents above have been tried and not worked for various reasons. It has low risk of mild side effects, but the risk of hypophosphatemia is increased over the two agents above.
4. Ferric carboxymaltose (Injectafer®): this is the most well-studied of iron types in RLS so it definitely works. One of the downsides is that it is more effective at 1000 mg and higher than over lower doses, but comes in packages of 750 mg. Most infusion centers would not want to eat the cost of two vials for one infusion of 1000 mg (wasting 500 mg) so it requires a second trip to get the other 750 mg. This makes it quite expensive at $1200 for 750 mg with two infusion center trips of unclear cost to the patient. The other big downside is that hypophosphatemia is common with this agent. Hypophosphatemia means low phosphorus levels, which is an important mineral involved in a wide variety of body functions, but low levels can cause muscle weakness and thinning of bones among other effects. Most of the time, the effects of hypophosphatemia are not serious, but this agent has become more controversial in RLS. Those with some specific medical conditions or needing repeated infusions throughout the year may be at greater risk for hypophosphatemia, and perhaps doctors should elect another type of iron. The jury is still out on this one despite studies showing it works well for RLS, but definitely worth getting for most patients above iron sucrose, ferric gluconate, or continuing oral iron when ineffective.
For now, this is my take on the types of IV iron available in the US, though I expect more and more research to come out as IV iron is increasingly used for RLS as each review paper and new guideline advocate more strongly for this treatment. A final important word on this: as alluded to in the first paragraph, insurance coverage for this procedure is close to non-existent. Most third parties will only cover the infusion if a patient meets criteria as having iron deficiency anemia. For RLS alone, it may be nowhere to be found in the “covered benefits” booklet or coverage policies at all and thus not reimbursed. Many patients with RLS may benefit from infusion but do not have iron levels low enough to meet criteria for anemia. Thus, many face the choice of no infusion or a hefty, unpredictable fee for out-of-pocket payment with these trumped-up medical center charges that are intended for fun and games with insurance companies and not for direct payment from patients. I have also experienced many independent infusion centers not even offering standalone IV iron because the reimbursement to them is too low to make any margin on the infusion, which is also a shame and further limits access to this crucial treatment. There are a huge number of those with bothersome RLS who could completely avoid any of the RLS medications and their many potential undesirable side effects, if they could just get an infusion without ever being exposed to a medication, most particularly in the case of dopamine agonists. It is time that the medical community, health systems, insurance liaisons of professional societies, and even patients help to iron out the problem of insurance coverage for this first-line treatment as soon as possible (told you, only one more iron-related pun after the first paragraph!).
-Andy Berkowski MD of ReLACS Health, who restrained himself from a large infusion of iron-related puns in this blog
