Are There Reasonable Alternatives to Daraparim (Pyrimethamine) for Toxoplasmosis?

There are 2 factors that now limit access to Turing Pharmaceutical’s Daraprim, a major and often-preferred component of treatment for toxoplasmosis: 1) its (at least) $750-per-pill cost; and 2) its restrictive “patient-access”* through ICSConnect or Walgreens Specialty Pharmacy. For instance, a patient’s medical insurance might balk at covering the list price for the drug, or financial relief might otherwise not be forthcoming. Or, because of the restrictive patient access, delay of treatment is inevitable.

In fact, guidelines for toxoplasmosis treatment currently advise, “[I]f pyrimethamine is unavailable or there is a delay in obtaining it [emphasis added], TMP-SMX [Bactrim] should be utilized in place of pyrimethamine-sulfadiazine or pyrimethamine-clindamycin.” Likewise, the US Department of Veterans Affairs advised on October 2nd that “the application process, approval, and delivery of [pyrimethamine] will take at least 2 days [emphasis added].” Therefore, “[f]or toxoplasmosis, the [Opportunistic Infections] Guidelines Panel recommends the use of trimethoprim-sulfamethoxazole (for patients not allergic to the components) until pyrimethamine can be obtained for use in preferred regimens (eg, pyrimethamine + sulfadiazine).” In fact, physicians at HIVClinician.org report their trouble with accessing Daraprim for their patients. These physicians have encountered significant treatment delays, and they have had to resort to alternative antimicrobial therapies.

Limiting access to Daraprim is something completely manufactured by Turing Pharmaceuticals. By raising the price of the drug to inaccessible levels and by restricting its distribution channels, the company has presented a monopolistic extortion to the American people–or at least a monopolistic extortion to those who are desperately ill with toxoplasmosis.

In response to plenty of public backlash, Turing, and specifically its CEO Martin Shkreli, claim that their price hike on a ~60-year-old drug, which cost less than $1/pill as recently as c2012 and was liberally available through retail pharmacies until recently, is intended to fund Turing’s future R&D. This, in my opinion, is a disingenuous rebuttal that merely adds insult to the current injury of limiting access to a longstanding FDA-approved drug. It’s a response that unfairly places the pharma revenue cart** before the R&D horse. At its essence, it’s a f*ck-you-pay-me-now shakedown cloaked in a longshot promise of delayed beneficence.

For patients, physicians, and insurers who can’t or aren’t willing to comply with this kind of medical extortion, the issue becomes one of finding reasonable treatment alternatives to pyrimethamine that don’t compromise medical care. Fortunately there appear to be several. (Although their presentation here should not be construed as medical advice.)

Imprimis (to the rescue)

First, in response to Turing’s price hike on Daraprim, Imprimis Pharmaceuticals is offering compounded formulations of pyrimethamine for only 99 cents per pill. These compounded formulations, which include leucovorin, are available through the Imprimis Cares program. Although Turing currently sells the only FDA-approved form of pyrimethamine in the United States, Imprimis can legally offer its version of pyrimethamine through its subsidiary compounding pharmacy. The situation is akin to the sale of compounded versions of hydroxyprogesterone when K-V Pharmaceuticals offered the only FDA-approved version of the drug (Makena), which was (and is) much more expensive than the compounded versions.

On the basis of the K-V/Makena case, the FDA will allow compounders to sell their versions of these longstanding generic drugs. As the agency reports here, it “generally prioritizes enforcement actions related to compounded drugs using a risk-based approach, giving the highest enforcement priority to pharmacies that compound products that are causing harm or that amount to health fraud.” In other words, the FDA doesn’t prohibit compounders in a blanket fashion from offering their versions of FDA-approved generic medications, but the agency will investigate individual compounders on the basis of some kind of cause (eg, a report of harm). So unless Imprimis messes up somehow and/or there’s a complaint against the company, the FDA will allow Imprimis to sell its compounded pyrimethamine.

What would be really nice, though, and a tremendous public service is if the FDA made a comparative analysis of Turing’s Daraprim and Imprimis’s compounded pyrimethamine, like the agency did with K-V’s Makena and compounded formulations of hydroxyprogesterone. As I’ve written elsewhere, I suspect that Turing and Imprimis get their API pyrimethamine from the same or a similar original source (ie, either Fukuzyu [in the case of Turing] or IPCA Laboratories). Therefore, I would suspect the drugs to be analytically equivalent. But it would be nice of have official confirmation.

One downside, however, of ordering Imprimis’s version of compounded pyrimethamine is that delivery of the drug takes at least 3 days, because the medication is made to order. Consequently, like in the case of Turing’s Daraprim, some kind of alternative treatment (eg, Bactrim) must be instituted until pyrimethamine can be obtained and given as part of a treatment regimen for systemic toxoplasmosis.

But the medical literature also offers alternative–and maybe even preferred–non-pyrimethamine regimens for toxoplasmosis.

Toxoplasma Retinochoroiditis

In their retrospective review published last year in the Journal of Ophthalmology, Harrell and Carvounis admitted, “There is no consensus as to what the best treatment for Toxoplasma retinochoroiditis might be.” On the basis of their examination of published, English-language clinical studies from 1946 to May of 2014, they found “conflicting evidence as to the effectiveness of systemic antibiotics” for the condition and “no evidence to support that one antibiotic regimen is superior to another.” Therefore, they advised that the choice of an antibiotic regimen for toxo retinochoroiditis should be based on the respective safety profiles of the various treatment options.

With respect to efficacy, they concluded that “trimethoprim-sulfamethoxazole may the best first-line treatment of Toxoplasma retinochoroiditis, with intravitreous clindamycin with dexamethasone an alternative for patients intolerant, unresponsive or with a contraindication (such as pregnancy) to trimethoprim-sulfamethoxazole.” Furthermore, there was level I evidence that intermittent (every 2-3 days) trimethoprim-sulfamethoxazole (160/800 mg) reduced the risk of disease recurrence.

The CDC, citing a c2011 source, advises,

Treatment for ocular diseases should be based on a complete ophthalmologic evaluation. The decision to treat ocular disease is dependent on numerous parameters including acuteness of the lesion, degree if inflamation, visual acuity, and lesion size, location, and persistance (for example, “classic therapy” for ocular toxoplasmosis, adults: pyrimethamine 100 mg for 1 day as a loading dose, then 25 to 50 mg per day, plus sulfadiazine 1 gram four times per day, plus folinic acid (leucovorin) 5-25 mg with each dose of pyrimethamine; pediatric dose: pyrimethamine 2 mg/kg first day then 1 mg/kg each day, plus sulfadiazine 50 mg/kg two times per day, plus folinic acid (leucovorin) 7.5 mg per day) for 4 to 6 weeks followed by reevaluation of the patient’s condition. Leucovorin protects the bone marrow from the toxic effects of pyrimethamine. If the patient has a hypersensitivity reaction to sulfa drugs, pyrimethamine plus clindamycin can be used instead. The fixed combination of trimethoprim with sulfamethoxazole has been used as an alternative, as well as other drugs such as atovaquone and pyrimethamine plus azithromycin, which have not been extensively studied (see: Montoya JG, Boothroyd JC, Kovacs JA. Toxoplasma gondii in Mandell, Douglas, and Bennett’s Principles and Preactice of Infectious Diseases, 7th, Edition, 2010. Mandell GL, Bennett JE, Dolin R, Eds. Churchill Livingstone Elsevier, Philadelphia, PA.; and de-la-Torre A, Stanford M, Curi A, Jaffe GJ, Gomez-Marin JE. Therapy for ocular toxoplasmosis. Ocul Immunol Inflamm. 2011;19:314-20. Corticosteroids are sometimes prescribed in addition to antiparasitic agents.

But keep in mind: Harrell and Carvounis noted that “[t]here have been significant additional contributions to the literature since [July 2011].” Furthermore, the CDC makes no comment on the current limitations on accessing pyrimethamine, either on the basis of the drug’s high cost or its restricted access/distribution. The absence of updated sources and any comments on access to pyrimethamine suggest that the CDC recommendations are not as current they could be.

As of this posting, 20 tablets of trimethoprim-sulfamethoxazole cost anywhere from $4.00 (Walmart) to $12.17 (CVS), or 20-61 cents per pill.

Toxoplasma Encephalitis

Another recently published study retrospectively examined an alternative regimen to the standard pyrimethamine-based treatment for cerebral toxoplasmosis in patients with HIV/AIDS. One reason for the alternative therapy: the irregular availability of pyrimethamine in West Bengal, India. After obtaining informed consent, the physicians used the combination of cotrimoxazole (Bactrim) and clindamycin on “compassionate grounds” over pyrimethamine/sulfadiazine. The outcomes: the alternative regimen was more efficacious and better tolerated than the standard regimen.

Outcome	Pyrimethamine/ Sulfadiazine (n = 16)	Cotrimoxazole/ Clindamycin (n = 25)	P Value
Complete response	31%	80%	.002
Treatment failure	44%	12%	.03
On-treatment mortality	38%	12%	.07
Drug-related adverse events	62%	24%	.02

Complete response = >50% improvement of clinical status or >50% decrease in size of brain lesions after 2 weeks of treatment initiation.

The most common complication associated with pyrimethamine/sulfadiazine was severe thrombocytopenia with major bleeding (4/16, 25%).  The authors concluded that cotrimoxazole/clindamycin “could be used in developing countries” or (to borrow a phrase from the article’s title) in a “resource-poor setting.”

Which raises an interesting question: Has Turing now made the United States a resource-poor setting when it comes to accessing FDA-approved pyrimethamine?

*Which, as far as I can tell, is merely intended to thwart generic competition. It certainly can’t be on the basis of safety issues (that is, from a REMS perspective), given that Daraprim is a ~60-year-old drug that was liberally available through retail pharmacies until Turing acquired the US marketing rights (or just before Turing acquired the US marketing rights).

**And what revenue it’ll be.