Pyrimethamine: Medical Uses, Contraindications, Side Effects, Interactions and Mechanism of Action

Marketed under the name Daraprim, it is a drug used with leucovorin to treat toxoplasmosis and cystodysporosis.

It is also used with dapsone as a second-line option to prevent Pneumocystis jirovecii pneumonia (formerly known as P. carinii) in people with HIV / AIDS.

It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.

Common side effects include gastrointestinal upset, severe allergic reactions, bone marrow suppression . It should not be used by people with a folate deficiency that has resulted in anemia.

There is concern that it may increase the risk of cancer. Although it is occasionally used during pregnancy, it is not clear if pyrimethamine is safe for the baby.

Pyrimethamine is classified as a folic acid antagonist. It works by inhibiting the metabolism of folic acid and therefore the production of DNA.

Your doctor will prescribe another medicine (folic / folinic acid) to prevent blood problems caused by pyrimethamine.

Pyrimethamine was discovered in 1952 and entered into medical use in 1953. It is on the World Health Organization’s Essential Medicines List, the most effective and safest medicines needed in a healthcare system.

In the United States in 2015 it was not available as a generic drug and the price increased from $ 13.50 to $ 750 per tablet ($ 75,000 for one treatment).

In other parts of the world it is available as a generic and costs as little as $ 0.05 to $ 0.10 per dose.

How to use the pyrimethamine tablet

Take this medication by mouth, usually once or twice a day, or as directed by your doctor. Take this medicine with food to decrease nausea and vomiting.

If vomiting is severe or continues, your doctor may lower your dose or instruct you to stop taking this medicine. Follow the explanations of your treating physician scrupulously.

Drink plenty of fluids to prevent kidney problems if you are taking a pyrimethamine medicine.

The pyrimethamine tablet works best when the amount of medicine in your system is kept at an unchanged level.

Therefore, take this medicine and other antiparasitics regularly, exactly as prescribed by your doctor. To help you remember, to take the pyrimethamine tablet at the same time each day.

The dose prescribed by the treating physician is based on your medical condition, the type of infection, the patient’s age, and response to treatment. How long you will take this medicine depends on your infection.

Your doctor must carefully adjust your dose to treat your infection and prevent serious side effects. Do not take more or less of the pyrimethamine medication than prescribed. Do not stop taking it before filling this prescription unless your doctor tells you to, even if you feel better.

Skipping or changing your dose without your doctor’s approval can increase the number of parasites, make the infection more difficult to treat (resistant), or worsen side effects.

Dosage and administration

Pyrimethamine is often given in combination with other medications.

Chemoprophylaxis of malaria : adults and children older than 10 years, 25 mg once a week; children 5 to 10 years, 12.5 mg once a week; infants and children under 5 years, 6.25 mg once a week.

Prophylaxis should begin 1 week before arrival in the endemic area and continue once a week. Upon returning to a non-malarial area, the dose should be maintained for another 4 weeks.

Regimens planned to include suppressive healing should extend through characteristic periods of early recrudescence and late relapses for at least 10 weeks in each case.

Treatment of acute attacks : use pyrimethamine in areas where only susceptible plasmodia exist. The drug is not recommended only in the treatment of acute attacks of malaria in non-immune people.

The fast-acting schizontocides (chloroquine, amodiaquine, quinacrine or quinine) are indicated for the treatment of acute attacks. However, the conjoint pyrimethamine dose of 25 mg daily for 2 days will initiate transmission control and suppressive cure.

In case of circumstances where pyrimethamine should be used alone in semi-immune people, the adult dose for an acute attack is 50 mg daily for 2 days; children 4 to 10 years old can receive 25 mg daily for 2 days.

In either case, clinical healing should be followed by the once-a-week regimen described above. Pyrimethamine should be co-administered with sulphalene or sulfadoxine as a single dose.

Adults and children over 14 years of age, 50 to 75 mg of pyrimethamine with 1 to 1.5 g of sulfalene or sulfadoxine; children 9 to 14 years old, 50 mg of pyrimethamine with 1 g of sulphalene or sulfadoxine.

Children 4-8 years old, 25 mg of pyrimethamine with 500 mg of sulphalene or sulfadoxine; children under 4 years, 12.5 mg of pyrimethamine with 250 mg of sulphalene or sulfadoxine.

A single dose is sufficient to eliminate asexual parasites from the blood of most patients.

Toxoplasmosis : Pyrimethamine should be administered simultaneously with sulfadiazine or another sulfonamide.

Adults and children over 6 years of age, a starting dose of 50 mg of pyrimethamine followed by 25 mg of pyrimethamine administered daily with 150 mg / kg (maximum 4 g) of sulfadiazine daily in 4 divided doses.

Children 2 to 6 years of age, a starting dose of 25 mg of pyrimethamine followed by 12.5 mg of pyrimethamine administered daily with 150 mg / kg (maximum 2 g) of sulfadiazine daily in 4 divided doses.

Children 10 months to 2 years, 12.5 mg of pyrimethamine administered daily with 150 mg / kg (maximum 1.5 g) of sulfadiazine daily in 4 divided doses.

Infants 3 to 9 months: 6.25 mg of pyrimethamine administered daily with 100 mg / kg (maximum 1 g) of sulfadiazine daily in 4 divided doses.

Infants younger than 3 months, 6.25 mg of pyrimethamine every other day given with 100 mg / kg (750 mg maximum) of sulfadiazine given in 4 divided doses every other day.

Treatment : treatment should be continued for 3 to 6 weeks. Your dose may need to be halved after you have been taking pyrimethamine for 1 to 3 weeks (after 2 to 4 days for a child).

If additional therapy is indicated, a period of 2 weeks should elapse between treatments. Take with food if pyrimethamine upsets your stomach or affects your appetite.

Medical uses

Pyrimethamine is usually given with a sulfonamide and folinic acid.

It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.

Toxoplasmosis

Pyrimethamine is also used in combination with sulfadiazine to treat active toxoplasmosis. The two drugs bind to the same enzyme targets as the drugs trimethoprim and sulfamethoxazole-dihydrofolate reductase and dihydropteroate synthase, respectively.

Pyrimethamine has also been used in several trials to treat retinochoroiditis.

Consideration of pregnancy

Pyrimethamine is labeled pregnancy category C in the United States. To date, there is insufficient evidence about its risks in pregnancy or its effects on the fetus.

Malaria

It is mainly active against Plasmodium falciparum, but also against Plasmodium vivax. Due to the emergence of strains of P. falciparum resistant to pyrimethamine, pyrimethamine alone is rarely used now.

In combination with a long-acting sulfonamide such as sulfadiazine, it was widely used, as in Fansidar, although resistance to this combination is increasing.

Contraindications and precautions

In areas of known or suspected resistance to pyrimethamine or related compounds, an alternative prophylactic should be used.

Although your doctor will prescribe folic / folinic acid to prevent low folate levels. Pyrimethamine is contraindicated in people with folate deficiency anemia.

Using pyrimethamine during pregnancy could harm an unborn baby. Use effective birth control to prevent pregnancy while taking this drug, and tell your doctor if you become pregnant.

Treatment is indicated only for women whose serological tests become positive during pregnancy and women who show increasing antibody titers against Toxoplasma during pregnancy.

Although the eyes are sometimes affected during an acute acquired attack, ocular toxoplasmosis is considered by most authorities to be a late manifestation of a congenital infection.

Therefore, in most cases, the eye disease does not reflect a danger to the fetus. Pregnant women should be treated only in the presence of increasing titers or if the eye injury threatens maternal vision.

Concurrent administration of folinic acid is recommended when pyrimethamine is used for the treatment of toxoplasmosis during pregnancy.

In toxoplasmosis, the risks resulting from the administration of high doses of pyrimethamine must be balanced against the dangers of abortion or fetal malformation due to infection.

Toxoplasmosis is believed not to infect the fetus before the sixth week of pregnancy and only rarely during early placentation.

Pyrimethamine should be used with caution in patients with liver or kidney disorders. Pyrimethamine can exacerbate folate deficiency due to innate disease or malnutrition.

When a sulphonamide is administered in combination, an adequate fluid intake should be ensured to minimize the risk of crystalluria.

The dose of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended dose of antimalarial and is close to the toxic level. If signs of folic acid deficiency appear, reduce the dose or discontinue the medication based on the patient’s response.

Folinic acid can be administered in a dose of 5 to 15 mg orally, iv, or im. daily for 3 days, or as needed to bring depressed platelet or white blood cell counts back to safe levels.

Advise patients to keep pyrimethamine out of the reach of children as accidental ingestion has resulted in death.

The recommended dose for the suppression of malaria should not be exceeded. In patients receiving a high dose, such as for the treatment of toxoplasmosis, weekly blood counts, including platelet counts, should be taken.

In patients with seizure disorders, a lower ‘starting’ dose (for toxoplasmosis) is recommended to avoid potential nervous system toxicity from pyrimethamine.

Side effects

Before using this medicine, tell your doctor or pharmacist your medical history, especially of:

Seizures, kidney problems, liver problems, a certain type of low red blood cell count (megaloblastic anemia due to low levels of folic acid).

Low levels of folic acid in other conditions (such as malnutrition, problems with food absorption, alcoholism), low red / white blood cell counts, low blood cell (platelet) count.

When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea.

A rash is also seen, which may be indicative of a hypersensitivity reaction, particularly in combination with sulfonamides. Effects on the central nervous system include ataxia, tremors, and seizures.

Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.

Some people using this medicine can develop serious side effects, including blood problems, especially at higher doses.

This risk can be reduced with the use of folic / folinic acid and regular blood tests. Tell your doctor right away if you have any of these symptoms:

Easy bruising / bleeding, signs of serious infection (such as high fever, severe chills, persistent sore throat), signs of low red blood cell count (such as severe tiredness, pale lips, nails and skin), fast heart rate, breathing with habitual activities, swollen / painful tongue.

Get medical help right away if you have very serious side effects, including: bloody / pink urine, chest pain, slow, fast, or irregular heartbeat.

If you notice other effects not listed above, contact your doctor or pharmacist.

Interactions

Interactions with other medications can change how pyrimethamine, its medications, work, or increase the risk of serious side effects.

Other antifolate agents such as methotrexate and trimethoprim can potentiate the antifolate actions of pyrimethamine, leading to possible folate deficiency, anemia, and other blood dyscrasias.

Some products that may interact with this drug include:

  • Lorazepam, penicilamina, sulfamidas (como sulfametoxazol).
  • Medicines that can lower folate levels (such as phenytoin, trimethoprim).
  • Medicines that can lower blood counts (such as proguanil, zidovudine, chemotherapy), including methotrexate, daunorubicin, and cytosine.

Mechanism of action

Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitive inhibition of the enzyme dihydrofolate reductase.

Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa. Pyrimethamine has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.

Other medications

Pyrimethamine is usually given with folinic acid and sulfadiazine.

Sulfonamides (eg, sulfadiazine) inhibit dihydropteroate synthetase, an enzyme that is involved in the synthesis of folic acid from para-aminobenzoic acid.

Therefore, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme necessary for the synthesis of folic acid.

Folinic acid (leucovorin) is a derivative of folic acid converted to tetrahydrofolate, the main active form of folic acid, in vivo, without depending on dihydrofolate reductase.

Folinic acid reduces the side effects related to folate deficiency in the patient.

Mechanism of resistance

Resistance to pyrimethamine is widespread. Mutations in the malaria gene for dihydrofolate reductase can reduce its effectiveness.

These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase through loss of hydrogen bonds and steric interactions.

History

Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to fight malaria. Pyrimethamine has been available since 1953.

In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014 and completed the acquisition, which includes Daraprim, in March 2015.

In August 2015, the rights were purchased by Turing Pharmaceuticals. Later, Turing became notorious for a price hike controversy when he raised the price of a dose of the drug in the U.S. market from $ 13.50 to $ 750, an increase of 5,500%.

Availability and price

In the United States, beginning in 2015, with the acquisition by Turing Pharmaceuticals of the United States marketing rights to Daraprim tablets, Daraprim became a single specialty pharmacy item and the price of Daraprim increased .

The cost of a monthly course for a person with a 75 mg dose increased to about $ 75,000 / month, or $ 750 per tablet.

Outpatients can no longer obtain Daraprim from their community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions can no longer order from their general wholesaler, but have to open an account with the Daraprim program Direct.

Presentations by Retrophin, a company headed by Martin Shkreli , CEO of Turing, from where Turing acquired the rights to Daraprim.

They suggest that a closed distribution system could prevent generic competitors from legally obtaining drugs for bioequivalence studies required by the Food and Drug Administration to approve a generic drug.

Martin Shkreli , CEO of Turing, defended the price hike by saying, “If there was a company that was selling an Aston Martin for the price of a bike, and we bought that company and asked it to charge Toyota prices, I wouldn’t.” . I think that should be a crime.

As a result of the backlash, Shkreli hired a public relations firm to help explain his fund’s move. Turing Pharmaceuticals announced on November 24, 2015 “that it would not reduce the list price of that drug after all,” but will offer various patient assistance programs.

However, New York Times reporter Andrew Pollack noted that these programs “are standard for companies that sell extremely expensive drugs. They allow patients to obtain the drug and at the same time pass most of the costs on to insurance companies and taxpayers.

The price increase has been fiercely criticized by medical groups such as HIV Medicine Associates and Infectious Disease Society of America.

In 2016, a group of Sydney Grammar high school students with the support of the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price increase unjustifiable.

Shkreli said the students were not in competition, likely because the necessary bioequivalence studies require a sample of the existing drug provided directly by the company, and not simply purchased from a pharmacy, which Turing might refuse to provide.

In India, more than a dozen pharmaceutical companies make and sell pyrimethamine tablets, and multiple combinations of generic pyrimethamine are available for a price ranging from US $ 0.04 to US $ 0.10 each (3-7 rupees ).

In the UK, the same drug is available from GSK at a cost of US $ 20 (£ 13) for 30 tablets (about $ 0.66 each).

In Australia, the drug is available in most pharmacies at a cost of US $ 9.35 (A $ 12.99) for 50 tablets (about US $ 0.18 each).

In Brazil, the drug is available for R $ 0.07 per pill, or around US $ 0.02.

In Canada, the drug was reported to have been discontinued in 2013, but hospitals can manufacture the drug in-house when needed.

As of December 2015, Daraprim imported into Canada directly from GlaxoSmithKline plc (GSK) UK and is available from an online pharmacy for US $ 2.20 per tablet.

In Switzerland, the drug is available for US $ 9.45 (CHF9.05) for 30 tablets (about US $ 0.32 per piece).

On October 22, 2015, Imprimis Pharmaceuticals announced that it has made available customizable compounded formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting at $ 99.00 for a 100-count bottle in the United States.

Investigation

In 2011, researchers discovered that pyrimethamine can increase the activity of β-hexosaminidase, which could slow the progression of late-onset Tay-Sachs disease. It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.