pirfenidone (Rx)

Brand and Other Names:Esbriet
  • Print

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 267mg

tablet

  • 267 mg
  • 801 mg

Idiopathic Pulmonary Fibrosis

Initial dose titration

  • Take with food
  • Days 1-7: 267 mg PO TID (801 mg/day)
  • Days 8-14: 534 mg PO TID (1602 mg/day)
  • Day 15 and thereafter (maintenance): 801 mg PO TID; not to exceed 2403 mg/day

Dosage Modifications

If patients experience significant adverse reactions (ie, gastrointestinal, photosensitivity reaction, rash), consider temporary dosage reductions or therapy interruptions of pirfenidone to allow for resolution of symptoms; discontinue if symptoms persist despite these interventions

CYP1A2 inhibitors

  • Strong inhibitors (eg, fluvoxamine, enoxacin): Reduce maintenance dose to 267 mg (1 capsule) TID
  • Moderate inhibitors (eg, ciprofloxacin): Reduce maintenance dose to 534 mg (2 capsules) TID (with ciprofloxacin 750 mg BID)

Elevated liver enzymes

  • AST/ALT >3 to ≤5 x ULN (without symptoms): Discontinue confounding medications, exclude other causes, repeat liver function tests as needed; the full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (eg, until liver chemistry tests are within normal limits), with subsequent retitration to the full dosage as tolerated
  • AST/ALT >5 x ULN or >3 times ULN with signs/symptoms of severe liver damage: Permanently discontinue; do not rechallenge

Hepatic impairment

  • Mild-to-moderate (Child Pugh A or B): Use caution; monitor and consider dosage modification or discontinuation as needed
  • Severe (Child Pugh C): Not recommended (not studied)

Renal impairment

  • Mild, moderate, or severe: Use caution; monitor and consider dosage modification or discontinuation as needed
  • ESRD requiring dialysis: No recommended (not studied)

Dosing Considerations

Conduct liver function tests before initiating therapy (also see Dosage Modifications and Cautions)

Safety and efficacy not established

Next:

Interactions

Interaction Checker

and pirfenidone

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 

            Contraindicated (4)

            • carbamazepine

              carbamazepine will decrease the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Use of strong CYP1A2 inducers should be discontinued before initiating pirfenidone and avoided during treatment

            • phenobarbital

              phenobarbital will decrease the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Use of strong CYP1A2 inducers should be discontinued before initiating pirfenidone and avoided during treatment

            • primidone

              primidone will decrease the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Use of strong CYP1A2 inducers should be discontinued before initiating pirfenidone and avoided during treatment

            • rifampin

              rifampin will decrease the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Use of strong CYP1A2 inducers should be discontinued before initiating pirfenidone and avoided during treatment

            Serious - Use Alternative (22)

            • abametapir

              abametapir will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP1A2 substrates. If not feasible, avoid use of abametapir.

            • aminolevulinic acid oral

              aminolevulinic acid oral, pirfenidone. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid administering other phototoxic drugs with aminolevulinic acid oral for 24 hr during perioperative period.

            • aminolevulinic acid topical

              pirfenidone, aminolevulinic acid topical. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Each drug may increase the photosensitizing effect of the other.

            • amiodarone

              amiodarone will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • cigarette smoking

              cigarette smoking will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • cimetidine

              cimetidine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • ciprofloxacin

              ciprofloxacin will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • diclofenac

              diclofenac will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • duloxetine

              duloxetine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • fluoxetine

              fluoxetine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • fluvoxamine

              fluvoxamine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating treatment and avoided during treatment; if strong CYP1A2 inhibitor is only option, dosage reduction recommended

            • gemfibrozil

              gemfibrozil will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • givosiran

              givosiran will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP1A2 substrates with givosiran. If unavoidable, decrease the CYP1A2 substrate dosage in accordance with approved product labeling.

            • methoxsalen

              methoxsalen will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • methyl aminolevulinate

              pirfenidone, methyl aminolevulinate. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Each drug may increase the photosensitizing effect of the other.

            • mexiletine

              mexiletine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • nifedipine

              nifedipine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • ofloxacin

              ofloxacin will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • primaquine

              primaquine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            • propofol

              propofol will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • tranylcypromine

              tranylcypromine will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration of pirfenidone and moderate CYP1A2 inhibitors result in moderately increased exposure to pirfenidone; if unable to avoid, decrease dose of moderate CYP1A2 inhibitor

            • zileuton

              zileuton will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use of strong CYP1A2 inhibitors should be discontinued before initiating pirfenidone and avoided during treatment; if strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended

            Monitor Closely (4)

            • cannabidiol

              cannabidiol, pirfenidone. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Owing to the potential for both CYP1A2 induction and inhibition with the coadministration of CYP1A2 substrates and cannabidiol, consider reducing dosage adjustment of CYP1A2 substrates as clinically appropriate.

            • fexinidazole

              fexinidazole will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • rucaparib

              rucaparib will increase the level or effect of pirfenidone by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP1A2 substrates, if clinically indicated.

            • stiripentol

              stiripentol, pirfenidone. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP1A2 inhibitor and inducer. Monitor CYP1A2 substrates coadministered with stiripentol for increased or decreased effects. CYP1A2 substrates may require dosage adjustment.

            Minor (0)

              Previous
              Next:

              Adverse Effects

              >10%

              Nausea (36%)

              Rash (30%)

              Upper respiratory tract infection (27%)

              Diarrhea (26%)

              Abdominal pain (24%)

              Headache (22%)

              Dyspepsia (19%)

              Dizziness (18%)

              Vomiting (13%)

              GERD (11%)

              Sinusitis (11%)

              1-10%

              Insomnia (10%)

              Weight decreased (10%)

              Arthralgia (10%)

              Photosensitivity (9%)

              Decreased appetite (8%)

              Pruritus (8%)

              Asthenia (6%)

              Dysgeusia (6%)

              Noncardiac chest pain (5%)

              AST/ALT ≥3 x ULN (3.7%)

              <1%

              AST/ALT ≥10 x ULN (0.3%)

              Postmarketing Reports

              Blood and lymphatic system disorders: Agranulocytosis

              Immune system disorders: Angioedema

              Hepatobiliary disorders: Drug-induced liver injury

              Previous
              Next:

              Warnings

              Contraindications

              None

              Cautions

              Photosensitivity and rash reported; avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure; additionally, instruct patients to avoid concomitant medications known to cause photosensitivity; dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash

              Nausea, vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain reported; incidence of gastrointestinal events reported to be highest early in the course of treatment (with highest incidence occurring during initial 3 months); may decrease over time; temporary dosage reductions or discontinuations may be required

              Drug-induced liver injury

              • Conduct liver function tests (ALT, AST, and bilirubin) before initiating, monthly for 6 months, and then q3months thereafter and, as clinically indicated
              • Patients treated with 2403 mg/day reported having higher incidence of elevated ALT/AST in clinical trials
              • Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice
              • Dosage modifications, interruption, or discontinuation may be necessary to reverse liver enzyme elevation

              Drug interaction overview

              Pirfenidone is a CYP1A2 substrate; discontinue moderate or strong CYP1A inhibitors before initiating pirfenidone and avoid use during therapy; if unable to avoid, pirfenidone dose reduction required

              Discontinue strong CYP1A2 inducers before initiating pirfenidone and avoid use during therapy; likely to decrease exposure and lead to loss of pirfenidone efficacy

              Smoking associated with decreased systemic exposure; encourage patient to quit smoking

              Previous
              Next:

              Pregnancy & Lactation

              Pregnancy: Data in pregnant women are insufficient to inform on drug associated risks for major birth defects and miscarriage

              Lactation: No information is available on presence of pirfenidone in human milk, effects of drug on breastfed infant, or effects of drug on milk production; lack of clinical data during lactation precludes clear determination of risk of pirfenidone to infant during lactation; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and potential adverse effects on breastfed child from pirfenidone or from underlying maternal condition

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

              Previous
              Next:

              Pharmacology

              Mechanism of Action

              Precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established

              Inhibits transforming growth factor (TGF)-beta, a chemical mediator that controls many cell functions including proliferation and differentiation

              Also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation

              Absorption

              Peak plasma time: 0.5-4 hr

              Food decreased the rate and extent of absorption; Cmax and AUC decreased by ~49% and 16% with food, respectively

              A reduced incidence of adverse reactions was observed in the fed group when compared with the fasted group; administered with food in clinical trials

              Distribution

              Protein bound: 58%

              Vd: 59-71 L

              Metabolism

              Metabolized in the liver by CYP1A2 to inactive metabolites

              Elimination

              Half-life: 3 hr

              Majority of dose excreted as 5-carboxy-pirfenidone metabolite (99.6%)

              Excretion: 80% urine

              Previous
              Next:

              Administration

              Oral Administration

              Take with food

              Take doses at same time each day

              Missed doses

              • If ≥14 days: Reinitiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage
              • If <14 days: Resume the dosage prior to the interruption
              Previous
              Next:

              Images

              BRAND FORM. UNIT PRICE PILL IMAGE
              Esbriet oral
              -
              267 mg capsule

              Copyright © 2010 First DataBank, Inc.

              Previous
              Next:

              Patient Handout

              Patient Education
              pirfenidone oral

              PIRFENIDONE - ORAL

              (pir-FEN-i-done)

              COMMON BRAND NAME(S): Esbriet

              USES: Pirfenidone is used to treat a certain lung disease called idiopathic pulmonary fibrosis (IPF). This disease causes the lungs to get scarred and become stiff, making it hard to breathe. Pirfenidone may help slow down the worsening of your IPF.

              HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start taking pirfenidone and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with food as directed by your doctor, usually 3 times a day. Taking pirfenidone with food may help decrease dizziness and nausea. To reduce your risk of side effects, your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Take this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.Tell your doctor if your condition worsens.

              SIDE EFFECTS: Tiredness, lack of energy, loss of appetite, weight loss, or changes in taste may occur. Dizziness, nausea, upset stomach, vomiting, diarrhea, or heartburn may also occur but taking pirfenidone with food may lessen these side effects. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Pirfenidone may rarely cause serious liver disease. Get medical help right away if you have any symptoms of liver damage, including: persistent nausea/vomiting, loss of appetite, stomach/abdominal pain, yellowing eyes/skin, dark urine.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

              PRECAUTIONS: Before taking pirfenidone tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, kidney disease (such as dialysis).This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).This medication may make you more sensitive to the sun. Limit your time in the sun. Avoid tanning booths and sunlamps. Use sunscreen and wear protective clothing when outdoors. Tell your doctor right away if you get sunburned or have skin blisters/redness.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

              DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Other medications can affect the removal of pirfenidone from your body, which may affect how pirfenidone works. Examples include rifamycins (such as rifampin), drugs used to treat seizures (such as phenytoin), among others.Cigarette smoking decreases blood levels of this medication. Tell your doctor if you smoke or if you have recently stopped smoking.

              OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

              NOTES: Do not share this medication with others.Laboratory and/or medical tests (such as weight, liver function tests) should be performed before you start treatment, periodically to monitor your progress, or to check for side effects. Consult your doctor for more details.

              MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.If you miss 14 days or more of treatment in a row, you may have to restart treatment with a lower dose. Ask your doctor for more details.

              STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

              Information last revised August 2021. Copyright(c) 2021 First Databank, Inc.

              IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

              Previous
              Next:

              Formulary

              FormularyPatient Discounts

              Adding plans allows you to compare formulary status to other drugs in the same class.

              To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

              Adding plans allows you to:

              • View the formulary and any restrictions for each plan.
              • Manage and view all your plans together – even plans in different states.
              • Compare formulary status to other drugs in the same class.
              • Access your plan list on any device – mobile or desktop.

              The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
              ST Step Therapy
              Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
              OR Other Restrictions
              Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
              Additional Offers
              Email to Patient

              From:

              To:

              The recipient will receive more details and instructions to access this offer.

              By clicking send, you acknowledge that you have permission to email the recipient with this information.

              Email Forms to Patient

              From:

              To:

              The recipient will receive more details and instructions to access this offer.

              By clicking send, you acknowledge that you have permission to email the recipient with this information.

              Previous
              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.