# High-Yield Drug Side Effects for USMLE (Ranked)

> What drug side effects are highest yield for USMLE?

Fifteen ranked drug-toxicity pairs, then organ-by-organ sections, teratogen and antidote tables, and the 2025-2026 US label and REMS changes that alter old answers.

The highest-yield drug side effects point to one drug or class: ACE inhibitor cough and angioedema, amiodarone lung and thyroid toxicity, aminoglycoside ototoxicity, statin myopathy, clozapine neutropenia, isoniazid neuropathy, doxorubicin cardiomyopathy, cyclophosphamide hemorrhagic cystitis and heparin-induced thrombocytopenia. Learn each drug's signature toxicity, its mechanism and its timing, because vignettes give a drug, an interval and a new finding.

## What drug side effects are highest yield for USMLE?

Rank a toxicity by three tests: does the finding point to one drug or class, is it dangerous enough for a boxed warning, and does the drug's own pharmacology explain it? Pairs that pass all three, such as bleomycin and pulmonary fibrosis, top any review list, and pharmacology makes up 10 to 20% of Step 1 items.

Stems give a drug started at a stated interval, a finding the known disease does not explain, and five plausible culprits. Read the medication list first, then check the clock: hours point to serotonin syndrome or an infusion reaction, days to two weeks to warfarin necrosis or heparin-induced thrombocytopenia, months to tardive dyskinesia. The [Pharmacology](/topics/pharmacology) hub groups the other drug classes.

## Ranked: the 15 drug-toxicity pairs to learn first

Rows follow editorial priority, uniqueness of the finding first and danger second, checked against current US labels.

| Rank | Drug | Signature toxicity | Why it happens | Vignette clue |
| --- | --- | --- | --- | --- |
| 1 | ACE inhibitors | Dry cough; angioedema | ACE is kininase II, so bradykinin builds up | Cough that settles on an ARB; lip swelling even years in |
| 2 | Amiodarone | Lung, thyroid and liver toxicity | Very long half-life (15 to 142 days) prolongs toxicity | Dyspnea with a low DLCO; blue-gray skin |
| 3 | Aminoglycosides | Nephrotoxicity; usually permanent ototoxicity | Worse with renal impairment and long courses | Hearing loss or imbalance after gentamicin plus a loop diuretic |
| 4 | Statins | Myopathy, rhabdomyolysis | Risk rises with interacting drugs | High CK after gemfibrozil or a macrolide joins simvastatin |
| 5 | Clozapine | Severe neutropenia; seizures; myocarditis | Boxed warnings; REMS requirements lifted in 2025 | Fever and sore throat in treatment-resistant schizophrenia |
| 6 | Isoniazid | Neuropathy; hepatitis | Pyridoxine depletion | Tingling feet on TB treatment |
| 7 | Doxorubicin | Dilated cardiomyopathy | Cumulative dose; iron-driven free radicals | Falling ejection fraction, even years later |
| 8 | Cyclophosphamide, ifosfamide | Hemorrhagic cystitis | Acrolein in the urine | Hematuria; mesna and hydration protect the bladder |
| 9 | Bleomycin | Pulmonary fibrosis | Lungs lack bleomycin hydrolase | Dyspnea after testicular cancer or Hodgkin lymphoma therapy |
| 10 | Heparin | HIT with thrombosis | Antibodies to platelet factor 4-heparin complexes | Platelets halve on day 5 to 10 (up to 14) with a new clot |
| 11 | Warfarin | Skin necrosis; embryopathy | Falling protein C | Necrotic skin within days, without heparin overlap |
| 12 | Lithium | Nephrogenic DI; hypothyroidism; tremor | Narrow therapeutic window | Toxicity after an NSAID, diuretic, ACE inhibitor or ARB |
| 13 | Carbamazepine | SIADH; marrow failure; SJS/TEN | HLA-B\*15:02 in Asian ancestry | Low sodium in a patient treated for trigeminal neuralgia |
| 14 | Spironolactone | Gynecomastia; hyperkalemia | Binds androgen receptors | Breast enlargement in a man with heart failure |
| 15 | Vancomycin | Infusion reaction; kidney injury | Rate-related histamine release | Upper-body flushing during a fast infusion |

Acetaminophen, fluoroquinolones, phenytoin, digoxin and metformin round out a top 20 and appear below or on linked pages.

## Cardiac toxicity: QT drugs, anthracyclines and trastuzumab

Drug-induced torsades de pointes starts with a long QT interval, and the culprits cluster in a few classes.

- **QT prolongers:** class IA, IC and III antiarrhythmics, macrolides, fluoroquinolones, azoles, phenothiazines, tricyclics, haloperidol (worst intravenously), ondansetron, citalopram above 40 mg a day and methadone, which carries a boxed warning. Low potassium or magnesium adds risk. Torsades gets 2 g of IV magnesium sulfate, pacing or isoproterenol, and defibrillation if sustained.
- **Doxorubicin:** cardiomyopathy in 1 to 2% at a cumulative 300 mg/m² and 6 to 20% at 500 mg/m², more above 550 mg/m², sometimes years later. Dexrazoxane, an iron chelator, is labeled for women with metastatic breast cancer who have received 300 mg/m² and will continue doxorubicin, not at initiation.
- **Trastuzumab:** heart failure, worst alongside an anthracycline, that often recovers; in the AC-TH arm of two pooled adjuvant trials, 90.3% of patients with symptomatic failure had full or partial LVEF recovery.
- **Digoxin:** nausea, green-yellow vision with halos and almost any arrhythmia, provoked by hypokalemia, hypomagnesemia, hypercalcemia or renal impairment.

## Lung toxicity: which drugs cause pulmonary fibrosis?

Bleomycin, amiodarone, busulfan, methotrexate and nitrofurantoin are the classic causes of drug-induced pulmonary fibrosis.

- **Bleomycin:** pulmonary toxicity in about 10% and fatal fibrosis in about 1%, more often above 400 units or age 70; keep FiO2 near room air during later surgery.
- **Amiodarone:** pneumonitis in up to 17% in some series, fatal about 10% of the time; get a baseline chest x-ray and DLCO.
- **Busulfan:** fibrosis 8 months to 10 years after starting, plus darker skin.
- **Methotrexate:** acute or chronic interstitial pneumonitis.
- **Nitrofurantoin:** acute fever, cough and eosinophilia, or chronic fibrosis after 6 months or more.

## Liver, kidney and ear toxicity

Hepatotoxicity, nephrotoxicity and ototoxicity questions reuse a short list of drugs.

- **Acetaminophen:** cytochrome P450 forms NAPQI, which glutathione neutralizes. Toxicity needs 150 mg/kg or more acutely, a 4-hour level of 150 mcg/mL or less without symptoms makes it very unlikely, and N-acetylcysteine works best within 8 hours.
- **Other liver injury:** isoniazid hepatitis is age-related and more likely with daily alcohol, and propylthiouracil and oral ketoconazole carry boxed liver warnings; valproate is covered in [seizure classification and antiepileptic drugs](/blog/seizure-classification-antiepileptic-drugs-usmle).
- **Kidney:** conventional amphotericin B causes hypokalemia, renal tubular acidosis and azotemia; saline loading helps, lipid formulations cause less, and the conventional form must never exceed 1.5 mg/kg a day. Cisplatin injury is cumulative, starts in the second week and lowers magnesium. NSAIDs remove prostaglandin support of renal perfusion and can cause interstitial nephritis. Tenofovir tubulopathy is in [HIV antiretroviral drugs](/blog/hiv-antiretroviral-drugs-usmle).
- **Ear:** aminoglycoside damage is usually permanent. Cisplatin causes high-frequency hearing loss in 40 to 60% of children, reduced by sodium thiosulfate for localized solid tumors, and furosemide ototoxicity follows rapid injection, renal failure or a co-prescribed aminoglycoside.

## Blood toxicity: neutropenia, hemolysis, megaloblastic anemia and HIT

Hematologic questions ask which cell line fell and which drug explains it.

| Finding | Drugs to know | Clue or rule |
| --- | --- | --- |
| Agranulocytosis | Clozapine, carbamazepine, methimazole, propylthiouracil, dapsone | Fever and sore throat; thionamide cases cluster in the first 3 months |
| Aplastic anemia | Carbamazepine, felbamate, chloramphenicol | Pancytopenia; chloramphenicol cases have ended in leukemia |
| G6PD hemolysis | Primaquine, tafenoquine, dapsone, rasburicase, nitrofurantoin, methylene blue | Heinz bodies; test G6PD before primaquine or tafenoquine and screen high-risk patients before rasburicase |
| Methemoglobinemia | Dapsone, rasburicase | Methylene blue, unless G6PD deficient |
| Megaloblastic anemia | Methotrexate, trimethoprim, phenytoin; metformin via vitamin B12 | Leucovorin rescues methotrexate |
| HIT | Unfractionated heparin far more than LMWH | Platelets fall by over half, usually after 5 to 10 days (up to 14), or by day 1 after heparin in the prior 100 days |
| Warfarin skin necrosis | Warfarin | Within a few days; 5 to 7 days of heparin overlap lowers the risk |

For HIT, stop every heparin source, flushes included, and start a non-heparin anticoagulant such as argatroban, bivalirudin, fondaparinux, apixaban or rivaroxaban. Low-molecular-weight heparin cross-reacts, and warfarin waits for platelet recovery because early use has caused limb gangrene.

## Neurologic and psychiatric toxicity

Neurologic adverse effects sort into neuropathy, seizures, movement disorders and the drug hyperthermia syndromes.

- **Neuropathy:** isoniazid (prevented by pyridoxine 25 to 50 mg a day), vincristine (fatal if given intrathecally), cisplatin (can start weeks after the last dose), paclitaxel and prolonged metronidazole; linezolid and fluoroquinolones are in [antibiotic mechanisms and coverage](/blog/antibiotic-mechanisms-coverage-usmle).
- **Seizures:** bupropion (avoid with seizure disorders, bulimia or anorexia), tramadol, clozapine, and flumazenil in benzodiazepine-dependent patients.
- **Dopamine blockers:** acute dystonia within days (IM benztropine), akathisia within weeks (propranolol) and tardive dyskinesia after months or years (VMAT2 inhibitors valbenazine or deutetrabenazine); metoclopramide's boxed warning caps reflux treatment at 12 weeks.

| Feature | Serotonin syndrome | Neuroleptic malignant syndrome |
| --- | --- | --- |
| Trigger | An SSRI plus tramadol, linezolid, an MAO inhibitor, a triptan or methylene blue | D2 blockers, including metoclopramide; abrupt levodopa withdrawal |
| Onset | 6 to 24 hours after a dose change | Over days, usually in the first 2 weeks |
| Muscles and reflexes | Clonus and hyperreflexia, worst in the legs | Severe generalized rigidity; reflexes often reduced |
| Other findings | Agitation, sweating, tachycardia, diarrhea, fever | Delirium first, fever often above 40 °C, labile blood pressure |
| Labs | Clinical diagnosis (Hunter criteria) | High CK, rhabdomyolysis |
| Treatment | Stop serotonergic drugs; benzodiazepines; cyproheptadine | Stop the drug; cooling; benzodiazepines, dantrolene, bromocriptine |

Anticholinergic toxicity adds dilated pupils, warm dry skin, urinary retention, ileus and delirium; physostigmine is reserved for pure anticholinergic poisoning and avoided in tricyclic overdose. Malignant hyperthermia follows succinylcholine or volatile anesthetics in carriers of ryanodine receptor variants and responds to dantrolene. Compare the first two in [serotonin syndrome vs NMS](/blog/2026-06-15-everything-you-need-to-know-about-serotonin-syndrome-vs-nms-for-step-1).

## Endocrine and metabolic toxicity

Lithium, amiodarone and a few water-balance drugs anchor the endocrine side of drug toxicity.

- **Lithium:** tremor, polyuria, nephrogenic diabetes insipidus, hypothyroidism and hypercalcemia; levels climb with NSAIDs, diuretics, ACE inhibitors and ARBs ([lithium for Step 1](/blog/2026-06-15-everything-you-need-to-know-about-lithium-for-step-1)).
- **Amiodarone:** hypothyroidism in up to 10% and hyperthyroidism in about 2%; the two thyrotoxicosis types are in [thyroid disorders](/blog/thyroid-disorders-usmle).
- **Hyponatremia:** SIADH from carbamazepine, SSRIs in older adults, vincristine and cisplatin; thiazides lower sodium too.
- **Nephrogenic diabetes insipidus:** lithium and demeclocycline; amphotericin B also impairs urine concentration.
- **Gynecomastia:** spironolactone (about 9% of men in RALES), cimetidine and ketoconazole.
- **Thiazides:** hyperglycemia, hyperuricemia, mild hypercalcemia and hypokalemia.

## Skin reactions: SJS/TEN, DRESS and HLA testing

Stevens-Johnson syndrome detaches under 10% of body surface area, overlap 10 to 30%, and toxic epidermal necrolysis over 30%. Both start a few days to 8 weeks after a new drug, show a positive Nikolsky sign and mucosal erosions, and need the drug stopped and admission, ideally to intensive care or a burn unit. Usual culprits are lamotrigine, carbamazepine, phenytoin, phenobarbital, allopurinol, sulfonamides, oxicam NSAIDs and nevirapine.

- **HLA-B\*15:02:** screen at-risk Asian ancestry before carbamazepine (boxed warning).
- **HLA-A\*31:01:** carbamazepine hypersensitivity in European, Korean and Japanese patients.
- **HLA-B\*58:01:** consider screening before allopurinol where the allele is common.
- **HLA-B\*57:01:** abacavir hypersensitivity.

DRESS combines fever, rash, lymphadenopathy or facial swelling, organ injury and often eosinophilia. Photosensitivity follows tetracyclines, fluoroquinolones, TMP-SMX, thiazides, amiodarone and voriconazole, and hydrochlorothiazide also raises squamous cell skin cancer risk.

## Muscle, bone and connective tissue toxicity

Statin myopathy becomes more likely with age 65 or older, uncontrolled hypothyroidism, renal impairment, higher doses and interacting drugs.

- **Statins:** simvastatin is contraindicated with strong CYP3A4 inhibitors, gemfibrozil, cyclosporine and danazol ([CYP450 inducers and inhibitors](/blog/2026-06-23-everything-you-need-to-know-about-cyp450-enzymes-inducers-inhibitors-for-step-1)); rare immune-mediated necrotizing myopathy persists after stopping, with anti-HMG-CoA reductase antibodies.
- **Fluoroquinolones:** boxed warning for tendinitis and tendon rupture.
- **Gingival overgrowth:** phenytoin, cyclosporine and calcium channel blockers.
- **Bone:** bisphosphonates can cause jaw osteonecrosis and atypical femoral fractures; long-term, high-dose heparin can cause osteoporosis.
- **Drug-induced lupus:** hydralazine, procainamide, isoniazid and minocycline cause arthralgia, fever and serositis, classically with antihistone antibodies (TNF inhibitors, sometimes with anti-dsDNA), resolving after the drug stops.

## Teratogens: drug, defect and when it matters

Teratogen questions name the drug, the defect or the timing, so learn all three together.

| Drug | Defect or fetal effect | When it matters |
| --- | --- | --- |
| ACE inhibitors, ARBs | Fetal renal failure, oligohydramnios, lung and skull hypoplasia | Second and third trimesters |
| Isotretinoin | Ear, eye, face, skull, brain, heart and thymus defects | Any exposure; iPLEDGE REMS |
| Thalidomide | Amelia, phocomelia, ear and heart defects | Even one dose; REMS |
| Valproate | Neural tube defects, lower IQ | Avoid if pregnancy is possible unless other drugs fail |
| Phenytoin | Fetal hydantoin syndrome: craniofacial, nail and digit changes | Pregnancy exposure |
| Lithium | Cardiac anomalies, especially Ebstein anomaly | Pregnancy exposure |
| Warfarin | Nasal hypoplasia, stippled epiphyses; brain defects | First trimester (about 5%); later CNS defects |
| Methotrexate | Embryo-fetal death and malformations | Contraindicated for non-cancer use |
| Mycophenolate | Pregnancy loss; ear, lip, palate and limb defects | First trimester |
| Tetracyclines | Permanent tooth staining, enamel hypoplasia | Second half of pregnancy to age 8 |
| NSAIDs | Oligohydramnios from fetal renal dysfunction; ductus closure | From about 20 weeks; ductus from 30 |
| Trastuzumab | Oligohydramnios, pulmonary hypoplasia | Within 7 months before or during pregnancy |

Two classic answers changed: in July 2021 FDA asked makers to drop its strongest warning, the contraindication, against statins in pregnancy (most patients still stop), and since October 2020 it advises avoiding NSAIDs from about 20 weeks, except low-dose aspirin. iPLEDGE still governs isotretinoin. Changes approved on 9 February 2026, taking effect 15 November 2026, formalize prescriber-permitted home pregnancy tests during and after treatment, allowed under enforcement discretion since 2023; pre-treatment tests stay in a medical setting.

## Antidotes: toxin, antidote and how it works

Antidote questions test the pairing plus the one mechanism that makes it work.

| Toxin | Antidote | How it works |
| --- | --- | --- |
| Acetaminophen | N-acetylcysteine | Restores glutathione to neutralize NAPQI |
| Opioids | Naloxone | Opioid antagonist; nasal spray sold over the counter |
| Benzodiazepines | Flumazenil | Competitive blocker; can provoke seizures |
| Organophosphates | Atropine plus pralidoxime | Muscarinic block; cholinesterase reactivation before aging |
| Anticholinergics | Physostigmine | Cholinesterase inhibitor; avoid in tricyclic overdose |
| Tricyclic antidepressants | Sodium bicarbonate | Alkalinizes serum (pH 7.5 to 7.55) to narrow the QRS |
| Digoxin | Digoxin immune Fab | Binds digoxin |
| Heparin | Protamine | Basic protein forms an inactive salt with heparin |
| Warfarin | Vitamin K plus 4-factor PCC | Replaces vitamin K-dependent factors |
| Dabigatran | Idarucizumab | Antibody fragment that binds dabigatran |
| Apixaban, rivaroxaban | Prothrombin complex concentrate (off-label) | Replaces clotting factors; andexanet alfa left the US market in December 2025 |
| Methanol, ethylene glycol | Fomepizole | Blocks alcohol dehydrogenase |
| Iron | Deferoxamine | Chelates iron |
| Cyanide | Hydroxocobalamin | Forms cyanocobalamin, excreted in urine |
| Methemoglobinemia | Methylene blue | Redox agent; contraindicated in G6PD deficiency |
| Methotrexate | Leucovorin; glucarpidase | Reduced folate; glucarpidase for levels above 1 micromole per liter with renal impairment |
| Beta-blockers | Glucagon | 3 to 5 mg IV, then an infusion |

On 18 December 2025 FDA concluded that andexanet alfa's risks, chiefly thromboembolic events, outweigh its benefits; AstraZeneca ended US sales on 22 December and has asked to withdraw the license. The 2020 ACC pathway names prothrombin complex concentrate when andexanet is unavailable. Clozapine has needed no REMS enrollment or neutrophil-count reporting since 24 February 2025 (FDA formally released the REMS on 13 June 2025), but its boxed warning and ANC monitoring remain.

## Named reactions and classic vignette patterns

A few toxicities have names that stems use as shortcuts.

- **Vancomycin infusion reaction**, the term replacing "red man syndrome": histamine-mediated flushing and itching of the face, neck and upper torso, made infrequent by infusing over at least 60 minutes.
- **Disulfiram-like reaction:** flushing, nausea and tachycardia when alcohol meets metronidazole, cefotetan or procarbazine; disulfiram itself blocks alcohol oxidation at the acetaldehyde stage.
- **Cinchonism:** quinine's tinnitus, hearing loss, headache, flushing, nausea and blurred or altered color vision.
- **Gray baby syndrome:** neonates glucuronidate chloramphenicol poorly, then develop distension, pallid cyanosis and collapse; Drugs@FDA lists every US chloramphenicol product, injection included, as discontinued.

> **If you only remember one thing:** attribute by uniqueness, then confirm by timing. Hours: serotonin syndrome or an infusion reaction. First days: acute dystonia or warfarin skin necrosis. Days 5 to 10, sometimes to 14: heparin-induced thrombocytopenia. Up to 8 weeks: SJS/TEN. Months or years: tardive dyskinesia, chronic nitrofurantoin lung, cumulative anthracycline damage.

## How USMLE tests drug side effects: traps

Items tend to hide the culprit in the medication list, and the tempting wrong answer usually ignores the mechanism.

- **Platelets fall from 260,000 to 110,000 on day 8 of heparin, with a new DVT:** HIT; start argatroban, not warfarin or enoxaparin.
- **ACE inhibitor angioedema treated as allergy:** epinephrine, glucocorticoids and antihistamines have not been shown to work for bradykinin swelling; stop the drug and protect the airway.
- **Physostigmine for a tricyclic overdose:** avoid it (classically "contraindicated"; asystole has been reported); alkalinize with sodium bicarbonate.
- **Outdated rules:** statins are no longer contraindicated in pregnancy, and clozapine no longer runs through a REMS.

## Worked vignette: the lithium level that doubled

A 58-year-old woman with bipolar I disorder has taken lithium for 6 years with levels between 0.6 and 0.9 mEq/L. Over 3 days she has developed a worsening tremor, unsteady gait, slurred speech, vomiting and confusion, and her lithium level is 2.3 mEq/L. A new medication was started 10 days ago. Which new medication most likely raised her lithium level?

- A. Acetaminophen for knee pain
- B. Acetazolamide for altitude sickness prevention
- C. Ibuprofen for knee pain
- D. Sodium bicarbonate tablets for heartburn
- E. Theophylline for COPD

**Answer: C.** The lithium label warns that NSAIDs raise steady-state lithium levels, naming indomethacin and piroxicam and extending the effect to other NSAIDs, including COX-2 inhibitors. Acetazolamide (B), sodium bicarbonate (D) and theophylline (E) increase urinary lithium excretion and lower the level, and acetaminophen (A) is not among the drugs the label lists as changing it. Her tremor, ataxia, slurred speech, vomiting and confusion fit toxicity above 1.5 mEq/L. Lithium has no specific antidote: stop it and the NSAID, hydrate with saline, and dialyze severe poisoning.

## Sources

- USMLE: [Step 1 content outline and specifications](https://www.usmle.org/exam-resources/step-1-materials/step-1-content-outline-and-specifications)
- StatPearls (NCBI Bookshelf): [Heparin-induced thrombocytopenia](https://www.ncbi.nlm.nih.gov/books/NBK482330/), [Serotonin syndrome](https://www.ncbi.nlm.nih.gov/books/NBK482377/), [Extrapyramidal side effects](https://www.ncbi.nlm.nih.gov/books/NBK534115/), [Tardive dyskinesia](https://www.ncbi.nlm.nih.gov/books/NBK448207/), [SJS and TEN](https://www.ncbi.nlm.nih.gov/books/NBK459323/), [Tricyclic toxicity](https://www.ncbi.nlm.nih.gov/books/NBK430931/), [Anticholinergic toxicity](https://www.ncbi.nlm.nih.gov/books/NBK534798/), [Drug-induced lupus](https://www.ncbi.nlm.nih.gov/books/NBK441889/)
- PubMed: [ASH 2018 HIT guideline](https://pubmed.ncbi.nlm.nih.gov/30482768/), [HIT timing review](https://pubmed.ncbi.nlm.nih.gov/20008202/)
- CDC: [Adverse events during TB treatment](https://www.cdc.gov/tb/hcp/treatment/adverse-events.html), [Choosing a drug to prevent malaria](https://www.cdc.gov/malaria/hcp/drug-malaria/index.html); NIDDK: [Diabetes insipidus](https://www.niddk.nih.gov/health-information/kidney-disease/diabetes-insipidus)
- ACC: [2020 decision pathway on bleeding with oral anticoagulants](https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2020/07/10/11/26/2020-ACC-Expert-Consensus-Decision-Pathway-on-Bleeding)
- Also checked on 7 October 2026: FDA pages on clozapine, andexanet, iPLEDGE, NSAIDs and statins; FDA's REMS database; Drugs@FDA; DailyMed labels; Merck Manual toxicology chapters; NEJM 2021 and CMAJ 2026 commentaries renaming the vancomycin reaction.

Make every drug-to-toxicity link automatic before test day: [Drill drug side effects with StepGenie pharmacology questions](https://dashboard.stepgenie.app/sign-up).

## Frequently asked questions

### Which drug side effects are tested most often on USMLE?

The pairs worth learning first are the ones where a single finding identifies a single drug or class: ACE inhibitor cough and angioedema, amiodarone lung and thyroid toxicity, aminoglycoside nephrotoxicity and ototoxicity, statin myopathy, clozapine neutropenia, isoniazid neuropathy, doxorubicin cardiomyopathy, cyclophosphamide hemorrhagic cystitis, bleomycin pulmonary fibrosis and heparin-induced thrombocytopenia. Pharmacology makes up 10 to 20% of Step 1 items, and stems usually pair a new finding with a drug started at a stated interval.

### How do you tell serotonin syndrome from neuroleptic malignant syndrome?

Serotonin syndrome usually appears 6 to 24 hours after a serotonergic dose change, often an SSRI combined with tramadol, linezolid, an MAO inhibitor or methylene blue, and shows clonus and hyperreflexia that are most obvious in the legs. Neuroleptic malignant syndrome develops over days on a dopamine blocker, with severe generalized rigidity, reduced reflexes, fever often above 40 °C and a high creatine kinase. Treat the first with benzodiazepines and cyproheptadine, the second with cooling plus dantrolene or bromocriptine.

### Which drugs cause pulmonary fibrosis?

Bleomycin, amiodarone, busulfan, methotrexate and nitrofurantoin are the classic causes. Bleomycin injures the lung because lung tissue lacks bleomycin hydrolase, with risk rising above 400 units and after age 70. Amiodarone causes pneumonitis in up to 17% of patients in some series. Busulfan lung can appear months to years after starting, methotrexate causes acute or chronic interstitial pneumonitis, and nitrofurantoin causes an acute hypersensitivity reaction or chronic fibrosis after 6 months or more.

### Does clozapine still require REMS monitoring?

No. Since 24 February 2025 FDA has not expected prescribers, pharmacies or patients to use the clozapine REMS or to report absolute neutrophil counts before dispensing; FDA formally released the REMS on 13 June 2025, and the current label no longer describes one. The boxed warning for severe neutropenia remains, starting clozapine is not recommended below a baseline ANC of 1,500/µL, and FDA still recommends monitoring ANC at the frequencies set out in the prescribing information.

### What reverses apixaban or rivaroxaban now that andexanet is gone?

Andexanet alfa is no longer sold in the US. On 18 December 2025 FDA concluded that its risks, chiefly thromboembolic events, outweigh its benefits; in the ANNEXA-I trial thrombosis occurred in 14.6% of patients on andexanet versus 6.9% on usual care by day 30. AstraZeneca ended US sales on 22 December and has asked to withdraw the license. The 2020 ACC decision pathway names prothrombin complex concentrate, used off-label, when andexanet is unavailable, while dabigatran keeps its own reversal agent, idarucizumab.

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