This page shows what was measured, who it was measured in, and what that does not settle.
What Terfenadine does in the body
The unconverted parent, which normally exists only in trace amounts, blocks the potassium channel the heart uses to reset between beats.
Terfenadine is converted in the liver, almost entirely and almost immediately, into a different molecule that blocks histamine receptors in the nose and skin without entering the brain. That metabolite is what actually relieves the symptoms. If anything stops the liver doing the conversion, the parent builds up and the heart rhythm can break down.
Why people take it. Formerly used for hay fever without causing drowsiness.
What happened in people
A common antifungal made the drug accumulate and changed heart readings in all six healthy volunteers tested.
✓ Reviewed first-read answer
Where this came from
A person wrote this and a reviewer approved it against this exact record. It carries no effect size.
A reviewer approved this against this record. The reviewed-claim record carrying the exact population and effect size does not exist yet.
No source is stored against this line.
The limit that matters most
Other newer allergy medicines did not show the same heart-channel effect.
Where it acts
Peripheral H1 receptors in nasal mucosa and skin; the toxicity site is the ventricular myocyte
Kind of result
The kind of result is not recorded
Supervision
Professional supervision is normally required. It is a prescription or clinician-administered medicine where it is approved.
What the registries record it as
Its recorded molecular formula is C32H41NO2, weighing 471.7.
PubChem record · 5405 · read 2026-08-29
Where each sentence above came from
A person wrote this explanation into the record, with the studies named in the path below.
A reviewer approved this sentence against this exact record and its sources.
The limit a reviewer approved as the one that matters most here.
The four opening statements run to 101 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Biomarker
A biomarker is a number from a test that stands in for something about health.
A picture of it, and where the picture fails
A biomarker is like a fuel gauge.
Where that stops being true. A gauge is wired to the tank. Many biomarkers are only loosely tied to health.
What people get wrong. A better number is read as a better life. Several medicines improved a number and helped nobody.
A measurable indicator used as a substitute for a clinical outcome of interest.
Placebo
A placebo is a dummy treatment given so the real one can be compared with it.
A picture of it, and where the picture fails
A placebo is like a blank control in an experiment.
Where that stops being true. A blank does nothing. People given a placebo often do get better.
What people get wrong. A placebo effect is read as imaginary. The improvement is measured and real.
An inactive intervention matched in appearance to the test intervention, used to control for non-specific effects.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Terfenadine and terfenadine carboxylate serum concentrations and corrected QT interval before and after adding ketoconazole
✓ The study showed what it set out to show
Who was studied
Terfenadine-ketoconazole interaction study (Honig et al.)
How many people
6
Study design
Prospective clinical pharmacology cohort, subjects as their own controls
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
All six subjects developed detectable unmetabolised terfenadine with associated QT prolongation; significant change in acid metabolite area under the curve
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Four of the six volunteers had their ketoconazole course shortened because of significant electrocardiographic repolarisation abnormalities. Only two completed the intended protocol.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet, 60 mg twice daily
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
Predisposing factors in reported torsades de pointes cases, and delayed rectifier potassium current block by parent versus metabolite
✓ The study showed what it set out to show
Who was studied
FDA Spontaneous Reporting System analysis with myocyte electrophysiology (Woosley et al.)
How many people
25
Study design
Spontaneous report analysis with in vitro mechanistic testing
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
Terfenadine equipotent with quinidine at the delayed rectifier current; terfenadine carboxylate inactive at 30-fold the terfenadine half-maximal concentration
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Spontaneous reports have no denominator, so 25 cases as of April 1992 establishes that the event occurs, not how often.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet, 60 mg twice daily
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
RNAWiki holds 2 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Terfenadine
What a person takes: Oral tablet, 60 mg twice daily.
The measurement behind this step
Twice-daily oral tablet subject to near-complete first-pass CYP3A4 metabolism to the active carboxylate. That single metabolic step is both the mechanism of action and the entire safety margin, which is why anything inhibiting CYP3A4 — azole antifungals, macrolide antibiotics, protease inhibitors, grapefruit juice — or any degree of hepatic impairment converts a well-tolerated drug into a proarrhythmic one.
Getting in
A tablet twice a day, and almost none of it survives the liver
Swallowed twice daily. Nearly all of it is converted on the first pass through the liver, so barely any of the original molecule ever reaches the bloodstream.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Oral 60 mg twice daily. Near-complete first-pass oxidation by CYP3A4 to terfenadine carboxylate, with parent drug typically below the limit of quantification in normal use.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
The metabolite reaches nose and skin, and not the brain
The converted molecule circulates to the tissues where allergy symptoms come from. It does not cross into the brain, which is why it does not cause drowsiness.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Terfenadine carboxylate is a zwitterion and a P-glycoprotein substrate, so it is effectively excluded from the central nervous system — the structural basis of non-sedation.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
The converted form blocks histamine receptors and relieves symptoms. The unconverted form blocks a heart potassium channel and does nothing useful.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Terfenadine carboxylate is an inverse agonist at the histamine H1 receptor. Terfenadine itself blocks hERG with an apparent dissociation constant of 350 nmol/L, ten-fold selectively over Kv1.5, and is equipotent with quinidine at the delayed rectifier current in isolated myocytes.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
Block the enzyme and the wrong molecule accumulates
An antifungal, an antibiotic or grapefruit juice can stop the conversion. Then the original drug builds up to levels that reach the heart.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
CYP3A4 inhibition by azoles, macrolides, protease inhibitors or furanocoumarins, or hepatic impairment or overdose, raises parent terfenadine towards and past the 350 nmol/L range. Reduced IKr prolongs ventricular repolarisation, widening the QT interval and permitting early afterdepolarisations.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
Hay fever relieved without drowsiness; torsades in the wrong combination
The antihistamine effect was excellent. In patients taking interacting drugs the heart rhythm could break down into a potentially fatal arrhythmia.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Measured endpoints: symptomatic relief of allergic rhinitis and urticaria without sedation, against QT prolongation in all six volunteers given concomitant ketoconazole and 25 spontaneous reports of torsades de pointes to the FDA as of April 1992.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Nobody. Its active metabolite, fexofenadine, is available over the counter worldwide and is the same antihistamine without the cardiac liability.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Where the result stopped carrying
Twenty-five torsades de pointes reports had reached the FDA by April 1992, seven years after approval
Dose restriction and interaction warnings preceded, and did not prevent, eventual withdrawal
Codified in the FDA withdrawn-for-safety list at 81 FR 69668 as "all drug products containing terfenadine"
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Withdrawn
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablet, 60 mg twice daily
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. It is a prescription or clinician-administered medicine where it is approved.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
A register records the withdrawal of an approval.
No source is stored against this line.
What is in the pack
Twice-daily oral tablet subject to near-complete first-pass CYP3A4 metabolism to the active carboxylate.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold. The rest of the recorded wording: That single metabolic step is both the mechanism of action and the entire safety margin, which is why anything inhibiting CYP3A4 — azole antifungals, macrolide antibiotics, protease inhibitors, grapefruit juice — or any degree of hepatic impairment converts a well-tolerated drug into a proarrhythmic one.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Withdrawn for QT prolongation and torsades de pointes. The measured harms are hERG block at an apparent dissociation constant of 350 nmol/L, potency equal to quinidine at the delayed rectifier current, and QT prolongation in all six volunteers given concomitant ketoconazole. Risk is concentrated in CYP3A4 inhibition, hepatic impairment and overdose. The antihistamine effect itself is carried entirely by the metabolite and is not implicated.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Where this came from
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequenc… · a recorded source, not a stored snapshot
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536 (8445816) · a recorded source, not a stored snapshot
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear∅Nothing found in the sources checked
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablet, 60 mg twice daily
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
A recorded note compares this form with the others that are sold. It is kept below, word for word.
§ A fixed RNAWiki sentence
Where this came from
Wording RNAWiki always uses, not a finding about this substance.
The recorded note, unchanged: That single metabolic step is both the mechanism of action and the entire safety margin, which is why anything inhibiting CYP3A4 — azole antifungals, macrolide antibiotics, protease inhibitors, grapefruit juice — or any degree of hepatic impairment converts a well-tolerated drug into a proarrhythmic one.
No source is stored against this line.
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine, withdrawn medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Terfenadine studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That near-complete first-pass metabolism gives a durable safety margin against a toxicity carried by the parent drug
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That QT prolongation is a class effect of second-generation antihistamines — loratadine, cetirizine, azelastine and fexofenadine were shown free of it
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
How much did people take in the studies?
The sources RNAWiki checked hold nothing for this field.
Why it matters. A result belongs to an amount. Without the amount the result floats free.
What would answer it
A stored source that records it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Terfenadine are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
Ketoconazole made all six volunteers accumulate the parent drug and prolong their QT
In plain words
Six healthy people took terfenadine for a week, then added a common antifungal. All six began accumulating the unconverted drug and their ECGs changed. Only two could finish the study.
What was measured
Unmetabolised terfenadine plasma concentration and corrected QT interval before and after ketoconazole
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Prospective cohort study with each subject as their own control: six healthy volunteers, four men and two women aged 24 to 35, taking no other medication, reached steady state on terfenadine 60 mg every 12 hours for seven days, then added ketoconazole 200 mg every 12 hours. All six had detectable levels of unmetabolised terfenadine after ketoconazole was added, associated with QT prolongation. Only two of the six could complete the full course of ketoconazole coadministration; four received a shortened course because of significant electrocardiographic repolarisation abnormalities. The area under the curve of the acid metabolite changed significantly. The authors' conclusion was that the combination should be avoided.
Written into the record, not signed off as a reviewed claim
The parent is as potent as quinidine; the metabolite does nothing to the channel
In plain words
Laboratory recordings showed the swallowed drug blocks the heart's potassium current as strongly as a classic anti-arrhythmic. The molecule it turns into does not block it at all, even at thirty times the concentration.
What was measured
Delayed rectifier potassium current block by terfenadine versus terfenadine carboxylate
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Woosley and colleagues examined FDA Spontaneous Reporting System cases — 25 reports of torsades de pointes as of 1 April 1992 — and then tested the resulting hypothesis in isolated feline myocytes. Terfenadine proved equipotent with quinidine as a blocker of the delayed rectifier potassium current. Terfenadine carboxylate, the major metabolite, did not inhibit that current even at concentrations 30 times higher than the terfenadine concentration producing a half-maximal effect. Their conclusion was that torsades de pointes results from a quinidine-like action of the parent drug plus factors that impair its normally rapid metabolism.
Source
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-1536
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
verified
Review state
Written into the record, not signed off as a reviewed claim
hERG identified as the specific channel, at 350 nanomolar
In plain words
Three years later the exact channel was named. Terfenadine blocks it at concentrations only a few times above what circulates in patients, and ten times more readily than the atrial channel.
What was measured
Apparent dissociation constant for hERG and Kv1.5 block by terfenadine
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Roy, Dumaine and Brown expressed Kv1.5 and hERG heterologously in Xenopus oocytes to compare sensitivity. hERG was ten times more sensitive than Kv1.5 to terfenadine block, with apparent dissociation constants of 350 nmol/L and 2.7 micromol/L respectively — values that agree with terfenadine block of IKr and IKur currents measured in human atrial myocytes. They noted the clinical relevance directly: terfenadine concentrations in human plasma may reach the 100 nmol/L range. Terfenadine carboxylate blocked neither channel. Their closing proposal — that hERG is likely the primary target for the cardiotoxic effects of other related antihistamines — was borne out by astemizole.
Written into the record, not signed off as a reviewed claim
Withdrawn and replaced by its own metabolite
In plain words
Rather than lose the drug entirely, the manufacturer licensed the molecule terfenadine turns into. Fexofenadine is now sold over the counter worldwide.
What was measured
Not recorded
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Because the antihistamine activity resides in terfenadine carboxylate and the cardiac liability resides in the parent, the clean solution was to market the metabolite directly. Fexofenadine was developed and licensed, and terfenadine was withdrawn; it now appears in the FDA's codified withdrawn-for-safety list at 81 FR 69668 as "all drug products containing terfenadine". This is the most complete resolution of any case in this file: the therapeutic benefit was preserved intact and the harm was removed, because the two lived in different molecules that happened to be linked by one metabolic step.
Written into the record, not signed off as a reviewed claim
Arrhythmia was assumed to be a class effect of non-sedating antihistamines. It is not
In plain words
After terfenadine and astemizole, the whole class fell under suspicion. Comparative testing showed loratadine, cetirizine and fexofenadine have no such effect.
What was measured
That QT prolongation and torsades de pointes are a class property of non-sedating H1 antihistamines
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
DuBuske reviewed the comparative evidence directly to test whether ventricular arrhythmia is a class effect of second-generation antihistamines. Electrocardiographic studies showed that terfenadine and astemizole, but not loratadine or cetirizine, prolong the QT interval in laboratory animals. In vitro, terfenadine and astemizole block cardiac potassium channels while neither loratadine nor desloratadine significantly inhibits them at clinically achievable blood levels. Human volunteer studies confirmed the absence of electrocardiographic effects of azelastine, cetirizine, fexofenadine and loratadine, given at several times the recommended dose or together with agents inhibiting their metabolism. The conclusion is explicit: the potential to cause ventricular arrhythmias is not a class effect.
Written into the record, not signed off as a reviewed claim
A drug with an enormous safety margin has none once the margin depends on an enzyme
In plain words
Under normal conditions almost no unconverted drug reaches the bloodstream, so the safety margin looked huge. That margin was not a property of the dose — it was a property of one liver enzyme continuing to work.
What was measured
That extensive first-pass metabolism provides a reliable safety margin against a toxicity carried by the parent drug
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Terfenadine undergoes near-complete first-pass metabolism by CYP3A4, so parent drug concentrations in normal use are very low relative to the 350 nmol/L hERG dissociation constant. That apparent margin was the basis on which the drug was considered safe. It is conditional rather than intrinsic: it disappears whenever CYP3A4 is inhibited by an azole antifungal, a macrolide antibiotic, grapefruit juice, or by hepatic impairment, and it disappears in overdose. Honig's study demonstrated the collapse experimentally in six healthy volunteers. The generalisable point is that a safety margin created by metabolism is only as robust as the metabolism, and prodrugs whose parent carries the toxicity have no floor beneath them.
Source
Honig PK et al., JAMA 1993;269:1513-1518; Woosley RL et al., JAMA 1993;269:1532-1536
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
Checks this page had to pass
✓ Passed
Identity resolved
no open identity hold
✓ Passed
No unresolved merge across substance families
no quarantine open
✓ Passed
Every public sentence names a source
The opening statement carries the origin: Written into the record, not signed off.
✗ Not passed
Trial roles classified for highlighted evidence
No registered study is classified as testing this substance.
✓ Passed
No internal keys in reader text
enforced by the copy-contract test over the rendered page
✓ Passed
Safety mode resolved
A register records the withdrawal of an approval.
✓ Passed
Canonical metadata present
slug and display name present
What is missing or unclear◇Read from sources, not yet reviewed
How this medicine reached us
Kept near the foot of the page. A historical event moves up only when it changes something about this substance today.
Withdrawn; no reason is published (RNAWiki)
What is missing or unclear◇Read from sources, not yet reviewed
What to learn next
Ordered by what would most change how you read this page, starting with what is easiest to misunderstand.
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What is not here
7 questions this page could not answer
These sections were prepared and left out because there was nothing to put in them. They are listed rather than hidden, so the gaps in this record are visible.
What was measured, goal by goal — found nothing in the sources checked.
How close this is to real life — found nothing in the sources checked.
Felt, measured, or meaningful — found nothing in the sources checked.
How long anything takes — found nothing in the sources checked.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
What changed on this page — found nothing in the sources checked.
The record as stored
The full record, for auditing
Everything above is built from what is below. This layer keeps the technical vocabulary, record identifiers and every stored row, so a reader who wants to check the page can.
The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A non-sedating antihistamine that turned out to be a prodrug whose parent molecule blocks the hERG channel as potently as quinidine while its active metabolite does not block it at all — so the drug was withdrawn and the metabolite was licensed in its place as fexofenadine.
Recorded evidence blocks (1)
Q2
Where do the label and the trials disagree about Terfenadine?
"withdrawn" against "approved": withdrawal status vs register status for Terfenadine.
✗ required summary fields resolved: 4 required field(s) not terminal: Why people use it, Best-supported result, Biggest unanswered question, Human evidence
✓ public claims reviewed: 0 reviewed claim(s); drafts are never rendered
✓ source coverage passed: 3 source rows
✓ no critical contamination: no quarantine open
✓ canonical metadata passed: slug and display name present
✓ no raw internal fields: enforced by the copy-contract test over the rendered page
This is a record of evidence. It is not medical advice, and it does not say this substance suits you. Nothing here says any substance on RNAWiki is appropriate for a child.