Drug & supplement interaction

Melatonin + Chlorpheniramine Polistirex, Codeine Polistirex

Chlorpheniramine Polistirex, Codeine Polistirex brand name: Tuzistra XR.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Chlorpheniramine Polistirex, Codeine Polistirex falls into 4 drug categories that Melatonin can interact with; the most serious is rated moderate. Theoretically, taking melatonin might increase the sedative effects of CNS depressants.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions4
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Chlorpheniramine Polistirex, Codeine Polistirex

These two interact in 4 distinct ways. Each one is explained separately below.

Why Are There 4 Interactions?

Melatonin interacts with whole categories of medication. Chlorpheniramine Polistirex, Codeine Polistirex falls into 4 of those categories, so it can interact with Melatonin in 4 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CNS DEPRESSANTS

1 of 4

Why this applies to Chlorpheniramine Polistirex, Codeine Polistirex

Chlorpheniramine Polistirex, Codeine Polistirex falls under CNS DEPRESSANTS — the group Melatonin interacts with.

Theoretically, taking melatonin might increase the sedative effects of CNS depressants.
Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing about combining melatonin with Tuzistra XR: this cough medicine already has two ingredients that make you drowsy. The codeine is an opioid, and the chlorpheniramine is a sedating antihistamine. Melatonin also nudges your body toward sleep, so stacking it on top can pile on the sleepiness.

In practice, that might mean feeling extra groggy, foggy-headed, dizzy, or slow the next morning. I want to be honest though, this concern is mostly theoretical, based on how these things work rather than strong studies. It's still worth a quick chat with your pharmacist or doctor, especially if you drive, take other calming medicines, or feel unusually knocked out. Never start or stop either one on your own.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed
Moderate

SEIZURE THRESHOLD LOWERING DRUGS

2 of 4

Chlorpheniramine Polistirex, Codeine Polistirex also falls under SEIZURE THRESHOLD LOWERING DRUGS.

Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.
Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the deal with combining melatonin and Tuzistra XR (which pairs codeine with the antihistamine chlorpheniramine). Both of these ingredients can, in theory, nudge the seizure threshold a little lower, meaning the brain may become slightly more prone to seizure activity. There's some clinical hint that melatonin itself may increase seizure frequency in a few people, especially children with existing neurological conditions. Stacking these together could add to that small risk.

I want to be honest though, this concern is mostly theoretical and based on pharmacology, not strong human studies. For most healthy adults using either short-term, it's unlikely to be a problem. But if you or your child has a seizure history, please check with your pharmacist or doctor before pairing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254. PubMed
  2. Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. Int J Neurosci 2001;107:77-85.. PubMed
Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

3 of 4

Chlorpheniramine Polistirex, Codeine Polistirex also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.
Laboratory research suggests that certain lots of melatonin inhibit CYP2D6. Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Minor Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's something a little tricky about Tuzistra XR. The codeine part actually relies on the liver enzyme CYP2D6 to turn into morphine, which is what gives the real pain and cough relief. Codeine is a prodrug, so it needs that enzyme to work. Lab studies hint that some batches of melatonin might slow down CYP2D6. If that happened, you could theoretically get a bit less morphine from the codeine, meaning slightly weaker relief, while the chlorpheniramine side could linger a touch longer.

Honestly, this is very weak, theoretical evidence from test-tube work, not real patients, and it's rated minor. I wouldn't lose sleep over it. The bigger real-world concern is that both melatonin and this medicine can make you drowsy, so combining them may leave you extra sleepy. Check with your pharmacist before pairing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed
Minor

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

4 of 4

Chlorpheniramine Polistirex, Codeine Polistirex also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.
Laboratory research shows that certain lots of melatonin inhibit CYP3A4. Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Minor Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the situation with Tuzistra XR, which pairs codeine with the antihistamine chlorpheniramine. There's lab-only evidence that some batches of melatonin may slow the CYP3A4 enzyme. Since chlorpheniramine is partly handled by that enzyme, the theory is that melatonin could let a little more of it linger in your body. With codeine, the bigger activation step actually runs through a different enzyme (CYP2D6), so the 3A4 angle matters less for the pain-relief part.

Practically speaking, this is a minor, theoretical concern. The main thing to watch is overlapping sleepiness, since melatonin, codeine, and chlorpheniramine can all make you drowsy. That stacked sedation, with possible dizziness or slowed breathing from the codeine, is worth more attention than the enzyme question. Please run it by your pharmacist or doctor before combining them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Melatonin Also Interacts With Other Medications

Melatonin has 1,115 moderate, 345 minor known drug interactions in our database — the Chlorpheniramine Polistirex, Codeine Polistirex one above is among them. If you take anything else, check it against the full list below.

Moderate 1,115 Minor 345 No known interaction 1,370 (incl. Chlorpheniramine Polistirex, Codeine Polistirex)
Taking anything else?

Check Another of Your Medications Against Melatonin

Covers the 2,830 medications we’ve checked against Melatonin. Pick one to open its full report.

From our Q&A

Questions About Melatonin or Chlorpheniramine Polistirex, Codeine Polistirex

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Melatonin or Chlorpheniramine Polistirex, Codeine Polistirex, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Chlorpheniramine Polistirex, Codeine Polistirex

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Chlorpheniramine Polistirex, Codeine Polistirex page lists 259 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Beer (major), Gamma-hydroxybutyrate (ghb) (major) and Grapefruit (major).

By severity: 12 major · 205 moderate · 42 minor.

Open the Chlorpheniramine Polistirex, Codeine Polistirex interaction page

One more smart check

Taking Melatonin as Part of a Dietary Supplement Product? Check It for Interactions

We hold 2,885 real supplement products containing Melatonin, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Melatonin. Your product may carry other ingredients that interact with Chlorpheniramine Polistirex, Codeine Polistirex too, on top of Melatonin — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Melatonin and Chlorpheniramine Polistirex, Codeine Polistirex Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Melatonin
Top 5%

#54 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Chlorpheniramine Polistirex, Codeine Polistirex
Steady interest

#2,809 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Melatonin

What is Melatonin?

Melatonin
  • Trouble falling asleep (insomnia)
  • Jet lag
  • Delayed sleep phase syndrome
  • Non-24-hour sleep-wake disorder
  • Shift-work sleep problems
  • Sleep problems in some children with conditions like autism or ADHD

Melatonin is a hormone your body makes naturally to help control your sleep-wake cycle, and the supplement form is widely used to help with sleep timing problems and jet lag. The evidence is strongest for certain circadian (body-clock) disorders and is more mixed for everyday insomnia. It is generally well tolerated for short-term use, but talk with your pharmacist or doctor before starting, especially for children or during pregnancy.

Read the full Melatonin monograph & all interactions
Keep checking

Other Drugs & Melatonin

Browse every other medication we’ve checked against Melatonin — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
1,115Moderate
345Minor
1,369No known interaction
1,115 Moderate 345 Minor 1,369 No interaction
Moderate

1,115 interactions

Showing 60 of 1,115 moderate interactions — see all 1,115 on the Melatonin page.

Minor

345 interactions

Showing 60 of 345 minor interactions — see all 345 on the Melatonin page.

No interaction 1,369 drugs checked — show the list

We also checked Melatonin against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,369 medications checked with no known interaction — see the full Melatonin list.

See the full Melatonin interactions page
See every supplement checked against Chlorpheniramine Polistirex, Codeine Polistirex, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Melatonin monograph › Uses, safety, and every drug interaction in one place Chlorpheniramine Polistirex, Codeine Polistirex supplement interactions › Every supplement checked against Chlorpheniramine Polistirex, Codeine Polistirex, ranked by severity Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Melatonin and Chlorpheniramine Polistirex, Codeine Polistirex Together: Common Questions

Can you take Melatonin with Chlorpheniramine Polistirex, Codeine Polistirex?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 4 interactions listed for Melatonin and Chlorpheniramine Polistirex, Codeine Polistirex?
Chlorpheniramine Polistirex, Codeine Polistirex belongs to more than one drug category, and Melatonin interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Melatonin and Chlorpheniramine Polistirex, Codeine Polistirex interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.