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STARTING TREATMENT

In this Patient Information Brochure, you will learn: • About the serious health concerns of • The importance of working with your doctor during your toxoplasmosis treatment • About getting started and the support available to you

Your doctor has prescribed DARAPRIM. DARAPRIM Read more about what you can expect What you need to know during treatment. Let’s get started!

DAR2016004, © May 2016 Turing Pharmaceuticals LLC. 1 01 ABOUT TOXOPLASMOSIS What is it and how is it contracted? • A serious infection caused by a parasite found in cat stool, raw meats, unwashed vegetables, water, and soil. • A parasite is an organism that lives on or in another (the “host”). Parasites survive by living off of their host. • Most people who have the parasite will not get seriously ill. However, in some people who have weakened immune systems, the parasite can cause serious illness. • The parasite most often affects the brain and eyes, but other organs such as the heart and the lungs can also be affected. • Toxoplasmosis can make you very sick and may even cause death.

INDICATION

DARAPRIM is a prescription medication that contains Not an actual patient pyrimethamine, indicated for the treatment of toxoplasmosis when used with a . NOTE: Do not use DARAPRIM if you: • are allergic to pyrimethamine or any component of DARAPRIM • have megaloblastic due to deficiency

What you need to know:

Toxoplasmosis is an infection caused by a parasite that most commonly causes a serious brain disease called . 2 3 02 STARTING TOXOPLASMOSIS TREATMENT What is DARAPRIM (pyrimethamine)? How can I get DARAPRIM?

DARAPRIM is a pill for the treatment of toxoplasmosis Your doctor will fax your DON’T FORGET to: that is used in combination with a sulfonamide (antibiotic). prescription to DARAPRIM • Provide a reliable phone DARAPRIM can cause a side effect () so Direct’s Specialty number to reach you. your doctor may prescribe another medication (folinic Mail Order Pharmacy. acid) for this purpose. • Answer the phone when A Case Manager will call a Case Manager calls. USUALLY you about available financial DARAPRIM SULFONAMIDE • Be available at the FOLINIC assistance programs and to ACID appropriate location schedule your DARAPRIM to sign for the delivery delivery. Your doctor will prescribe the medication that is right of your DARAPRIM for you. It is very important to follow your doctor’s DARAPRIM will be medication. treatment plan. delivered to a convenient location for you. Please make sure INDICATION to answer the phone when DARAPRIM DARAPRIM is a prescription medication that contains Direct’s Specialty Mail pyrimethamine, indicated for the treatment of Order Pharmacy calls. toxoplasmosis when used with a sulfonamide. Not an actual patient NOTE: DARAPRIM is not for everyone. Do not take DARAPRIM if you are allergic to pyrimethamine or have anemia due to folate deficiency. At the first appearance of a skin rash you should stop use of DARAPRIM and seek medical attention immediately. Other symptoms that may be early indications of serious disorders include sore throat, paleness, and purple spots on skin or swollen tongue.

See pages 8-9 for Important Safety Information

4 5 03 STAYING ON YOUR TREATMENT PLAN Stick to your treatment plan as prescribed by your doctor.

What happens if you don’t take your medicine as prescribed?

It is important to make sure you take your medication as prescribed. If you do not take your medication as directed, your health may worsen.

Life gets busy and routines change, so let your doctor know if you’re having trouble taking your medication regularly.

Here are a few tips that can help you stay on top of your treatment:

• Let your medication become part of your daily routines so you’ll be less likely to forget it.

• Set an alarm on your phone, or put a sticky note on your door, to remind you to take your medication with you when you’ll be away from home.

• Answer calls from the Specialty Mail Order Not an actual patient Pharmacy and respond to their refill reminders so you don’t run out of pills.

• Financial help may be available so that cost does not prevent you from taking your medication.

• Stay engaged. If you’re taking multiple medications, don’t let it become overwhelming. Speak with your doctor about your concerns.

6 7 04 IMPORTANT SAFETY INFORMATION INDICATION Tell your healthcare provider if you have any side effects while DARAPRIM is a prescription medication that contains taking DARAPRIM. pyrimethamine for the treatment of: Notify your healthcare provider if you become pregnant or • Toxoplasmosis or acute when used with a sulfonamide intend to become pregnant during therapy or if you intend to (e.g., ) breast-feed or are breast-feeding an infant. • DARAPRIM is not for use by itself to treat acute malaria Tell your healthcare provider if you have problems with your and only for patients infected in areas where susceptible or , decreased intestinal absorption problems, plasmodia (the parasite that causes malaria) exist. Other alcoholism, or any other medical conditions. medicines such as or are preferred for Make sure you tell your healthcare provider about all of the the treatment of acute malaria prescription and non-prescription medications you take, • For prevention of malaria when the plasmodia is susceptible. including supplements, and especially sulfonamides or It is not suitable as a prophylactic agent for travelers - combination, (another to most areas since resistance to pyrimethamine is prevalent antimalarial medicine), zidovudine (a medicine to treat Human worldwide Immunodeficiency Virus, HIV), or cytostatic agents (medicines that block cell division e.g., , a medicine used for IMPORTANT SAFETY INFORMATION cancer or rheumatoid arthritis), phenytoin (a medicine to treat Do not use DARAPRIM if you: seizures), or lorazepam (a medicine to treat anxiety). • are allergic to pyrimethamine or any component of DARAPRIM Be sure to take your medicine as instructed. Do not exceed the recommended dosage. You may take DARAPRIM with • have megaloblastic anemia due to folate deficiency or without food. However, taking DARAPRIM with food may Taking DARAPRIM may result in allergic reactions that can be minimize associated anorexia and vomiting. severe (such as Stevens-Johnson syndrome, toxic epidermal Keep out of the reach of infants and children: necrolysis, erythema multiforme, and anaphylaxis). Symptoms Deaths in pediatric patients have been reported after of an allergic reaction or the severe reactions may include: accidental ingestion. fever, body aches, facial or tongue swelling, skin pain, peeling of skin, blisters on your skin and mucous membranes, itching, Note: The above information for patients being treated with rash, red itchy welts, wheezing, asthma symptoms, or dizziness DARAPRIM is intended to aid in the safe and effective use of or feeling faint. At the first appearance of a skin rash or any of this medication. It is not a disclosure of all possible adverse or the above symptoms, stop the medication and immediately intended effects. Please read the accompanying Full Prescribing seek medical attention. Other signs and symptoms of serious Information and talk to your healthcare provider for more disorders may include sore throat, paleness, tongue changes, information concerning your treatment if you have questions. and purple skin color. You are encouraged to report negative side effects of Make sure to tell your healthcare provider if you have any heart prescription drugs to the FDA. Visit www.fda.gov/medwatch conditions, especially if you experience irregular heartbeat. or call 1-800-FDA-1088. To report SUSPECTED ADVERSE The most common side effects that may occur with DARAPRIM REACTIONS contact Turing Pharmaceuticals at 1-877-258-2033. include allergic reactions (see above), blood disorders (including neutropenia or a low level of neutrophils, a white blood cell Please See Accompanying Full Prescribing Information important to fight off infections), tongue changes, blood in the DARAPRIM is a licensed trademark urine, heart rhythm disorders, anorexia, and vomiting. of Turing Pharmaceuticals AG.

8 9 05 DARAPRIM DIRECT—A TRUSTED RESOURCE

The DARAPRIM Direct Program was created to help you obtain quick and affordable access to DARAPRIM. Not actual patients Through enrollment in the DARAPRIM Direct program, you may be able to benefit from a range of financial assistance programs.1

• Uninsured patients have access to DARAPRIM for no out-of-pocket cost through the patient assistance program. • Through co-pay assistance, patients with commercial insurance are not obligated to pay more than $10 out-of-pocket for their DARAPRIM prescription. • Patients with Medicare Part D insurance coverage have access to an independent charitable foundation that may assist with affordability of their disease treatment. Be sure to sign the patient authorization on the DARAPRIM Enrollment Form (HIPAA form) to allow a Case Manager to assess your eligibility.

1Financial assistance programs are subject to terms and conditions and patient eligibility requirements. Restrictions, including where prohibited by law, may apply. Offers are subject to change or discontinuance without notice. Financial assistance programs are not insurance nor are they intended to be a substitute for insurance.

10 11 06 ADDITIONAL TOXOPLASMOSIS INFORMATION

CDC http://www.cdc.gov/parasites/toxoplasmosis/ http://www.cdc.gov/parasites/toxoplasmosis/gen_ info/faqs.html 1-800-CDC-INFO (1-800-232-4636) TTY: 1-888-232-6348

Medicine.net http://www.medicinenet.com/script/main/mobileart. asp?articlekey=7812

Mayo Clinic http://www.mayoclinic.org/diseases-conditions/ toxoplasmosis/basics/definition/con-20025859

Harvard http://www.patienteducationcenter.org/articles/ toxoplasmosis/ Not an actual patient

To learn more about DARAPRIM, visit daraprimdirect.com

12 13 07 WHAT YOU NEED TO REMEMBER

You have received a DARAPRIM prescription. How long do I have to take my medication? Your DARAPRIM Direct’s Specialty Mail Order Your doctor will determine how long you will need to take Pharmacy will arrange delivery of your medication DARAPRIM. It is extremely important that you take your and provide information on any financial assistance medication exactly as your doctor tells you. programs that may be available to you.

How do I get my medication? What are the 3 most important things I must remember to do to get my medication? Answer your phone when a Case Manager calls to tell you that your medication is ready for delivery. Prov ide a reliable phone number to reach you. It is very important that you answer this call so that Answer the phone when a Case Manager calls. you can receive your medication. A Case Manager will schedule when you will receive Be available at the appropriate location to sign for the your medication and at the most convenient location. delivery of your DARAPRIM medication. Make sure you are available to sign for the delivery of your medication. DON’T FORGET YOUR NEXT APPOINTMENT

How do I take my medication? Dr ______• You will likely be prescribed more than one Location: ______medication as part of your treatment. • Always take all of the medications as your doctor Date: ______has directed. Time: ______• Finish your full course of therapy even if you are feeling better. DARAPRIM may cause negative side effects. Speak to your doctor for more information.

14 15 08

NOTES ______DARAPRIM ______What you need to know ______© 2016 Turing Pharmaceuticals LLC | December 2016 | DAR2016095 16 DARAPRIM® (pyrimethamine) 25 mg transmission control and suppression of sore throat, pallor, purpura, or may tablets susceptible strains of plasmodia. be early indications of serious disorders which Rx Only Chemoprophylaxis of Malaria: require treatment with DARAPRIM to be DARAPRIM is indicated for the stopped and medical treatment to be sought. PRESCRIBING INFORMATION chemoprophylaxis of malaria due to Women of childbearing potential who are susceptible strains of plasmodia. However, taking DARAPRIM should be warned against DESCRIPTION resistance to pyrimethamine is prevalent becoming pregnant. Patients should be DARAPRIM (pyrimethamine) is an worldwide. It is not suitable as a prophylactic warned to keep DARAPRIM out of the reach compound available in tablet agent for travelers to most areas. of children. Patients should be advised not to form for oral administration. Each scored exceed recommended doses. Patients should be tablet contains 25 mg pyrimethamine and the CONTRAINDICATIONS warned that if anorexia and vomiting occur, they inactive ingredients corn and potato starch, Use of DARAPRIM is contraindicated in may be minimized by taking the drug with meals. lactose, and magnesium stearate. patients with known hypersensitivity to Concurrent administration of is Pyrimethamine, known chemically as 5-(4- pyrimethamine or to any component of the strongly recommended when used for the chlorophenyl)-6-ethyl-2,4- formulation. Use of the drug is also treatment of toxoplasmosis in all patients. pyrimidinediamine, has the following contraindicated in patients with documented Laboratory Tests: In patients receiving high structural formula: megaloblastic anemia due to folate deficiency. dosage, as for the treatment of toxoplasmosis, semiweekly blood counts, including platelet counts, should be performed. C12H13ClN4 WARNINGS Mol. Wt. 248.71 The dosage of pyrimethamine required for the Drug Interactions: Pyrimethamine may be treatment of toxoplasmosis is 10 to 20 times used with sulfonamides, quinine and other the recommended antimalaria dosage and antimalarials, and with other antibiotics. CLINICAL PHARMACOLOGY approaches the toxic level. If signs of folate However, the concomitant use of other Pyrimethamine is well absorbed with peak antifolic drugs or agents associated with levels occurring between 2 to 6 hours deficiency develop (see ADVERSE REACTIONS), reduce the dosage or myelosuppression including sulfonamides or following administration. It is eliminated trimethoprim-sulfamethoxazole combinations, slowly and has a plasma half-life of discontinue the drug according to the response of the patient. Folinic acid (leucovorin) proguanil, zidovudine, or cytostatic agents approximately 96 hours. Pyrimethamine is 87% (e.g., methotrexate), while the patient is bound to human plasma proteins. should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal receiving pyrimethamine, may increase the Microbiology: Pyrimethamine is a folic acid risk of bone marrow suppression. If signs of antagonist and the rationale for its therapeutic hematopoiesis is restored. Data in 2 humans indicate that pyrimethamine folate deficiency develop, pyrimethamine action is based on the differential requirement may be carcinogenic; a 51-year-old female should be discontinued. Folinic acid between host and parasite for nucleic acid who developed chronic granulocytic (leucovorin) should be administered until precursors involved in growth. This activity is leukemia after taking pyrimethamine for 2 normal hematopoiesis is restored (see highly selective against plasmodia and years for toxoplasmosis3 and a 56-year-old WARNINGS). Mild hepatotoxicity has been Toxoplasma gondii. patient who developed reticulum cell sarcoma reported in some patients when lorazepam and Pyrimethamine possesses blood after 14 months of pyrimethamine for pyrimethamine were administered schizonticidal and some tissue schizonticidal toxoplasmosis.4 concomitantly. activity against malaria parasites of humans. Pyrimethamine has been reported to produce Carcinogenesis, Mutagenesis, Impairment However, the 4-amino-quinoline compounds a significant increase in the number of lung of Fertility: See WARNINGS section for are more effective against the erythrocytic tumors in mice when given intraperitoneally information on carcinogenesis. schizonts. It does not destroy gametocytes, at doses of 25 mg/kg.5 Mutagenesis: Pyrimethamine has been but arrests sporogony in the mosquito. DARAPRIM should be kept out of the reach shown to be nonmutagenic in the following in The action of pyrimethamine against of infants and children as they are extremely vitro assays: the Ames point mutation assay, Toxoplasma gondii is greatly enhanced when susceptible to adverse effects from an the Rec assay, and the E. coli WP2 assay. It used in conjunction with sulfonamides. This overdose. Deaths in pediatric patients have was positive in the L5178Y/TK +/- mouse was demonstrated by Eyles and Coleman1 in been reported after accidental ingestion. lymphoma assay in the absence of exogenous the treatment of experimental toxoplasmosis metabolic activation.6 Human blood in the mouse. Jacobs et al2 demonstrated that PRECAUTIONS lymphocytes cultured in vitro had structural combination of the 2 drugs effectively General: The recommended dosage for chromosome aberrations induced by prevented the development of severe uveitis chemoprophylaxis of malaria should not be pyrimethamine. in most rabbits following the inoculation of exceeded. A small “starting” dose for In vivo, chromosomes analyzed from the bone the anterior chamber of the eye with toxoplasmosis is recommended in patients marrow of rats dosed with pyrimethamine toxoplasma. with convulsive disorders to avoid the showed an increased number of structural and potential nervous system toxicity of numerical aberrations. INDICATIONS AND USAGE pyrimethamine. DARAPRIM should be used Pregnancy: Teratogenic Effects: Pregnancy Treatment of Toxoplasmosis: DARAPRIM with caution in patients with impaired renal or Category C. Pyrimethamine has been shown is indicated for the treatment of toxoplasmosis hepatic function or in patients with possible to be teratogenic in rats when given in oral when used conjointly with a sulfonamide, folate deficiency, such as individuals with doses 7 times the human dose for since synergism exists with this combination. malabsorption syndrome, alcoholism, or chemoprophylaxis of malaria or 2.5 times the DARAPRIM Treatment of Acute Malaria: pregnancy, and those receiving therapy, such human dose for treatment of toxoplasmosis. is also indicated for the treatment of acute as phenytoin, affecting folate levels (see At these doses in rats, there was a significant malaria. It should not be used alone to treat Pregnancy subsection). increase in abnormalities such as cleft palate, acute malaria. Fast-acting schizonticides such Information for Patients: Patients should be brachygnathia, oligodactyly, and as chloroquine or quinine are indicated and warned that at the first appearance of a skin microphthalmia. Pyrimethamine has also preferable for the treatment of acute malaria. rash they should stop use of DARAPRIM and been shown to produce terata such as However, conjoint use of DARAPRIM with a seek medical attention immediately. Patients meningocele in hamsters and cleft palate in sulfonamide (e.g., sulfadoxine) will initiate should also be warned that the appearance of miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for OVERDOSAGE For Treatment of Acute Malaria: chemoprophylaxis of malaria or for treatment Following the ingestion of 300 mg or more of DARAPRIM is NOT recommended alone in of toxoplasmosis. pyrimethamine, gastrointestinal and/or the treatment of acute malaria. Fast-acting There are no adequate and well-controlled central nervous system signs may be present, schizonticides, such as chloroquine or quinine, studies in pregnant women. DARAPRIM including convulsions. The initial symptoms are indicated for treatment of acute malaria. should be used during pregnancy only if the are usually gastrointestinal and may include However, DARAPRIM at a dosage of 25 mg potential benefit justifies the potential risk to abdominal pain, nausea, severe and repeated daily for 2 days with a sulfonamide will the fetus. vomiting, possibly including hematemesis. initiate transmission control and suppression Concurrent administration of folinic acid is Central nervous system toxicity may be of non-falciparum malaria. DARAPRIM is strongly recommended when used for the manifest by initial excitability, generalized only recommended for patients infected in treatment of toxoplasmosis during pregnancy. and prolonged convulsions which may be areas where susceptible plasmodia exist. Nursing Mothers: Pyrimethamine is followed by respiratory depression, Should circumstances arise wherein excreted in human milk. Because of the circulatory collapse, and death within a few DARAPRIM must be used alone in semi- potential for serious adverse reactions in hours. Neurological symptoms appear rapidly immune persons, the adult dosage for acute nursing infants from pyrimethamine and from (30 minutes to 2 hours after drug ingestion), malaria is 50 mg for 2 days; children 4 concurrent use of a sulfonamide with suggesting that in gross overdosage through 10 years old may be given 25 mg DARAPRIM for treatment of some patients pyrimethamine has a direct toxic effect on the daily for 2 days. In any event, clinical cure with toxoplasmosis, a decision should be central nervous system. should be followed by the once-weekly made whether to discontinue nursing or to The fatal dose is variable, with the smallest regimen described below for discontinue the drug, taking into account the reported fatal single dose being 375 mg. There chemoprophylaxis. Regimens which include importance of the drug to the mother (see are, however, reports of pediatric patients who suppression should be extended through any WARNINGS and PRECAUTIONS: have recovered after taking 375 to 625 mg. characteristic periods of early recrudescence Pregnancy). There is no specific to acute and late relapse, i.e., for at least 10 weeks in Pediatric Use: See DOSAGE AND pyrimethamine poisoning. In the event of each case. ADMINISTRATION section. overdosage, symptomatic and supportive For Chemoprophylaxis of Malaria: Geriatric Use: Clinical studies of measures should be employed. Gastric lavage Adults and pediatric patients over 10 years – DARAPRIM did not include sufficient is recommended and is effective if carried out 25 mg (1 tablet) once weekly numbers of subjects aged 65 and over to very soon after drug ingestion. Parenteral Children 4 through 10 years – 12.5 mg (½ determine whether they respond differently diazepam may be used to control convulsions. tablet) once weekly from younger subjects. Other reported clinical Folinic acid should be administered within 2 Infants and children under 4 years – 6.25 mg hours of drug ingestion to be most effective in (¼ tablet) once weekly. experience has not identified differences in counteracting the effects on the hematopoietic responses between the elderly and younger system (see WARNINGS). Due to the long HOW SUPPLIED: patients. In general, dose selection for an half-life of pyrimethamine, daily monitoring White, scored tablets containing 25 mg elderly patient should be cautious, usually of peripheral blood counts is recommended pyrimethamine, imprinted with starting at the low end of the dosing range, for up to several weeks after the overdose “DARAPRIM” and “A3A” in bottles of 100 reflecting the greater frequency of decreased until normal hematologic values are restored. (NDC 69413-330-10) and bottles of 30 hepatic, renal, or cardiac function, and of (NDC 69413-330-30). concomitant disease or other drug therapy. DOSAGE AND ADMINISTRATION Store at 15° to 25°C (59° to 77°F) in a dry For Treatment of Toxoplasmosis: The place and protect from light. ADVERSE REACTIONS dosage of DARAPRIM for the treatment of Hypersensitivity reactions, occasionally toxoplasmosis must be carefully adjusted so REFERENCES severe (such as Stevens-Johnson syndrome, as to provide maximum therapeutic effect and 1. Eyles DE, Coleman N. Synergistic effect of toxic epidermal necrolysis, erythema a minimum of side effects. At the dosage and Daraprim against multiforme, and anaphylaxis), and required, there is a marked variation in the experimental toxoplasmosis in the mouse. hyperphenylalaninemia, can occur tolerance to the drug. Young patients may Antibiot Chemother 1953;3:483-490. particularly when pyrimethamine is tolerate higher doses than older individuals. 2. Jacobs L, Melton ML, Kaufman HE. administered concomitantly with a Concurrent administration of folinic acid is Treatment of experimental ocular sulfonamide. Consult the complete strongly recommended in all patients. toxoplasmosis. Arch Ophthalmol. prescribing information for the relevant The adult starting dose is 50 to 75 mg of the 1964;71:111-118. sulfonamide for sulfonamide-associated drug daily, together with 1 to 4 g daily of a 3. Jim RTS, Elizaga FV. Development of adverse events. With doses of pyrimethamine sulfonamide of the sulfapyrimidine type, e.g. chronic granulocytic leukemia in a patient used for the treatment of toxoplasmosis, sulfadoxine. This dosage is ordinarily treated with pyrimethamine. Hawaii Med J. anorexia and vomiting may occur. Vomiting continued for 1 to 3 weeks, depending on the 1977;36:173-176. may be minimized by giving the medication response of the patient and tolerance to 4. Sadoff L. Antimalarial drugs and Burkitt’s with meals; it usually disappears promptly therapy. The dosage may then be reduced to lymphoma. Lancet. 1973;2:1262-1263. upon reduction of dosage. Doses used in about one half that previously given for each 5. Bahna L. Pyrimethamine. LARC Monogr toxoplasmosis may produce megaloblastic drug and continued for an additional 4 to 5 Eval Carcinog Risk Chem. 1977;13:233-242. anemia, leukopenia, , weeks. 6. Clive D, Johnson KO, Spector JKS, et al. pancytopenia, neutropenia, atrophic glossitis, The pediatric dosage of DARAPRIM is 1 Validation and characterization of the hematuria, and disorders of cardiac rhythm. mg/kg/day divided into 2 equal daily doses; L5178Y/TK +/- mouse lymphoma mutagen Hematologic effects, however, may also after 2 to 4 days this dose may be reduced to assay system. Mut Res. 1979;59:61-108. occur at low doses in certain individuals (see one half and continued for approximately 1 PRECAUTIONS; General). month. The usual pediatric sulfonamide Distributed by: Turing Pharmaceuticals LLC Pulmonary eosinophilia has been reported dosage is used in conjunction with New York, New York 10036 rarely. DARAPRIM. 004967-PI-003 017602 Rev. 10/2016

DAR2016062 November 2016