Boxed warnings

IV: risk of medication errors and hepatotoxicity. Dosing errors, such as confusing mg with mL, weight-based errors under 50 kg, or misprogrammed pumps, can cause accidental overdose and death. Acetaminophen has caused acute liver failure, sometimes leading to transplant or death, mostly at doses above the daily maximum and often from more than one acetaminophen product.

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Oral Pacerone: pulmonary, hepatic, and cardiac toxicity. Use only for the labeled life-threatening arrhythmias, after other agents. Lung toxicity occurs in up to 17% in some series and is fatal about 10% of the time; get a baseline chest X-ray and pulmonary function tests and repeat the X-ray every 3 to 6 months. Liver injury can be fatal; check transaminases and reduce or stop if they rise above three times normal. It can worsen arrhythmias, so start it where continuous ECG and resuscitation are available. The Nexterone IV label has no boxed warning.

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In short-term trials in major depressive disorder and other psychiatric disorders, antidepressants raised the risk of suicidal thinking and behavior in children, adolescents, and young adults. No increase was seen in adults over 24, and risk fell in adults 65 and older. Monitor all patients closely for clinical worsening, suicidality, or unusual behavior changes, and enlist families and caregivers. Not approved for pediatric patients.

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Two warnings. (A) Stopping early raises the risk of clots and stroke; if it is stopped for any reason other than pathological bleeding or a finished course, cover with another anticoagulant. (B) Spinal or epidural hematoma, which can cause long-term or permanent paralysis, may occur with neuraxial anesthesia or spinal puncture. Risk rises with indwelling epidural catheters, other drugs affecting hemostasis, traumatic or repeated punctures, and prior spinal deformity or surgery. Monitor neurologic status often.

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Serious, sometimes fatal skin reactions (SJS and TEN), about 10 times more common in some Asian countries and strongly linked to HLA-B*1502. Screen patients with at-risk ancestry before starting, and do not treat allele-positive patients unless the benefit clearly outweighs the risk. Aplastic anemia and agranulocytosis occur 5 to 8 times more often than in the general population; get complete baseline blood counts, monitor closely if counts fall, and consider stopping for significant bone marrow depression.

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Fluoroquinolones can cause disabling, possibly permanent reactions that may occur together: tendinitis and tendon rupture, peripheral neuropathy, and CNS effects. Stop ciprofloxacin at once and avoid all fluoroquinolones after any of these. It can worsen myasthenia gravis; avoid it in patients with that history. Reserve it for patients without other options in bronchitis flares, uncomplicated cystitis, and acute sinusitis.

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Reduced effect in CYP2C19 poor metabolizers. Clopidogrel works only after CYP2C19 converts it to its active form. Patients with two loss-of-function CYP2C19 alleles make less active metabolite and get less platelet inhibition. Genetic tests can identify them; consider another P2Y12 inhibitor for these patients.

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Severe neutropenia with a risk of serious, potentially fatal infection: get a baseline ANC and do not start if it is below 1500/μL (below 1000/μL with benign ethnic neutropenia). Orthostatic hypotension, bradycardia, syncope, and cardiac arrest, highest during initial titration and after interruptions; start at 12.5 mg once or twice daily and titrate slowly in divided doses. Dose-related seizures. Fatal myocarditis, pericarditis, and cardiomyopathy. Higher mortality in older adults with dementia-related psychosis.

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Spinal or epidural hematomas. Patients on LMWH who receive neuraxial anesthesia or a spinal puncture can develop hematomas that cause long-term or permanent paralysis. Risk rises with indwelling epidural catheters, NSAIDs, platelet inhibitors or other anticoagulants, traumatic or repeated punctures, and prior spinal deformity or surgery. Monitor neurologic status often and treat compromise urgently.

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Nephrotoxicity and neurotoxicity. Gentamicin can damage the kidneys and both the hearing and balance branches of the eighth cranial nerve; ear damage is usually irreversible. Risk rises with renal impairment, high doses, prolonged therapy, older age, dehydration, and other nephrotoxic or ototoxic drugs. Monitor renal function and eighth nerve function, and serum levels when feasible: avoid prolonged peaks above 12 mcg/mL and troughs above 2 mcg/mL. Avoid potent diuretics such as furosemide. Aminoglycosides can harm the fetus.

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Increased mortality in elderly patients with dementia-related psychosis. Antipsychotic-treated older adults with dementia had about 1.6 to 1.7 times the risk of death of placebo patients, mostly from cardiovascular causes or infections. Haloperidol is not approved for dementia-related psychosis.

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Serious and life-threatening risks: addiction, abuse, and misuse that can lead to overdose and death; life-threatening respiratory depression, highest at the start and after dose increases; profound sedation, respiratory depression, coma, and death with benzodiazepines, alcohol, or other CNS depressants; neonatal opioid withdrawal syndrome after prolonged use in pregnancy; fatal overdose from accidental ingestion, especially by children; and oral solution dosing errors from mg and mL confusion.

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Cardiovascular thrombotic events: NSAIDs raise the risk of serious, possibly fatal heart attack and stroke, which may start early in treatment and grow with longer use; contraindicated around CABG surgery. Gastrointestinal risk: NSAIDs raise the risk of serious, possibly fatal GI bleeding, ulcers, and perforation, which can occur at any time without warning; older adults are at greater risk.

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Severe and sometimes fatal hepatitis can occur, even after many months of therapy. Risk is age related (about 23 per 1,000 at ages 50 to 64) and higher with daily alcohol use, chronic liver disease, injection drug use, and in women, particularly Black and Hispanic women and after delivery. Interview patients monthly; for those 35 and older, measure AST and ALT before starting and periodically. Strongly consider stopping if liver tests rise beyond 3 to 5 times the normal upper limit, stop promptly for symptoms of liver injury, and defer preventive therapy in acute liver disease.

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Cigarette smoking and serious cardiovascular events. Smoking raises the risk of serious cardiovascular events from combined hormonal contraceptives, and the risk climbs with age, especially over 35, and with the number of cigarettes smoked. Tyblume is contraindicated in women over 35 who smoke.

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Not for obesity or weight loss. Replacement doses do not reduce weight in people with normal thyroid function, and larger doses can cause serious or life-threatening toxicity, especially with sympathomimetic appetite suppressants.

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Fetal toxicity. Drugs acting on the renin-angiotensin system can injure or kill a developing fetus. Stop lisinopril as soon as pregnancy is detected.

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Lithium toxicity. Toxicity tracks closely with serum levels and can occur at doses near the therapeutic range. Do not start treatment unless prompt, accurate serum lithium testing is available.

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Use with opioids can cause profound sedation, respiratory depression, coma, and death; limit doses and durations and monitor closely. Benzodiazepines carry risks of abuse, misuse, and addiction. Continued use causes physical dependence; abrupt stop or rapid dose cuts can cause life-threatening withdrawal, so taper gradually.

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Fetal toxicity. Drugs acting on the renin-angiotensin system can injure or kill the developing fetus. Stop losartan as soon as pregnancy is detected.

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Lactic acidosis. Rare but can be fatal, with a subtle onset of malaise, myalgias, breathing trouble, sleepiness, and abdominal pain. Risk rises with renal impairment, age 65 or older, iodinated contrast, surgery, hypoxic states, heavy alcohol use, hepatic impairment, and drugs such as topiramate. If suspected, stop metformin, give supportive care in hospital, and start hemodialysis promptly.

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Embryo-fetal toxicity, hypersensitivity, severe adverse reactions, and medication errors. It can cause fetal death and is contraindicated in pregnancy for non-neoplastic diseases; patients treated for cancer need effective contraception. It is contraindicated after severe hypersensitivity, including anaphylaxis. Serious and fatal toxicity of the marrow, GI tract, liver, lungs, skin, and kidneys calls for close monitoring and withholding or stopping as appropriate. Taking it once daily by mistake has caused deaths.

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Abuse, misuse, and addiction. Methylphenidate has a high potential for abuse and misuse that can progress to a substance use disorder, including addiction. Misuse can cause overdose and death, with higher risk at higher doses or when snorted or injected. Assess abuse risk before prescribing, teach patients and families about safe storage and disposal, and keep reassessing and monitoring for signs of misuse throughout treatment.

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Metronidazole was carcinogenic in mice and rats. Avoid unnecessary use and reserve it for the labeled indications.

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Serious neuropsychiatric events, including agitation, aggression, depression, sleep disturbances, and suicidal thoughts and behavior, including suicide. Benefits may not outweigh risks when symptoms are mild; reserve for allergic rhinitis that has not responded to or tolerated other therapies. Teach patients and caregivers to watch for behavior changes and to stop the drug and call a provider right away if they occur.

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Serious and life-threatening risks: addiction, abuse, and misuse that can lead to overdose and death; life-threatening respiratory depression, highest at the start and after dose increases; profound sedation, respiratory depression, coma, and death with benzodiazepines, alcohol, or other CNS depressants; and neonatal opioid withdrawal syndrome after prolonged use in pregnancy.

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Not indicated for elective induction of labor, meaning induction without a medical indication, because available data do not establish its benefits against its risks for that use.

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IV and IM injection have caused fatal hypersensitivity reactions, including anaphylaxis, during or right after the dose, even when diluted and on the first dose. Give it subcutaneously unless that route is not feasible and the serious risk of IV or IM use is justified.

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Older adults with dementia-related psychosis treated with antipsychotics have a higher risk of death; quetiapine is not approved for them. Antidepressants raised suicidal thoughts and behavior in children, teens, and young adults; monitor all patients for worsening or suicidality. Not approved under age 10.

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Risk of thyroid C-cell tumors. Semaglutide causes these tumors in rodents; whether it causes medullary thyroid carcinoma in humans is unknown. Contraindicated with a personal or family history of MTC or with MEN 2. Teach patients to report a neck mass, trouble swallowing, shortness of breath, or lasting hoarseness.

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Suicidal thoughts and behaviors. Antidepressants raised the risk of suicidal thinking and behavior in children and young adults in short-term trials. Watch all patients closely for worsening or new suicidality.

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Risk of thyroid C-cell tumors. Tirzepatide causes dose- and duration-dependent thyroid C-cell tumors in rats; whether it causes medullary thyroid carcinoma in humans is unknown. Contraindicated with a personal or family history of MTC or with MEN 2. Counsel patients to report a neck mass, trouble swallowing, shortness of breath, or lasting hoarseness.

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Life-threatening adverse reactions. Hepatotoxicity, including fatal liver failure, usually in the first 6 months; children under 2 and patients with mitochondrial disorders are at higher risk, so check liver tests before and frequently during therapy. Fetal risk: neural tube defects, other major malformations, and decreased IQ. Pancreatitis, including fatal hemorrhagic cases.

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Bleeding risk. Warfarin can cause major or fatal bleeding. Monitor INR regularly in everyone. Drugs, diet, and other factors change the INR, and patients must be taught how to prevent and report bleeding.

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