FDA Requires Boxed Warnings for Deadly Opioid-Benzo Combo Risks

The FDA is adding its strongest possible warnings to the drug labeling of prescription opioid pain medications, opioid cough medicines, and benzodiazepines concerning serious adverse effects seen with concomitant use.

In a recent drug safety announcement, the FDA reported that combining opioids with benzodiazepines or other drugs that depress the central nervous system (CNS) can cause life-threatening adverse effects, such as slowed or difficult breathing and death. Past studies have shown a heightened risk of deadly drug overdose with the combined use of these medications. Meanwhile, the FDA conducted 2 studies that uncovered an increasing trend in concomitant dispensing of opioids and benzodiazepines, as well as an increase in combined prescription opioid-benzo abuse, misuse, and overdose.

In light of these findings, the FDA is adding new Boxed Warnings and revising the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of both drug classes’ labeling to warn health care professionals and patients about these risks. The agency is also requiring new or revised Medication Guides for patients.

Health care professionals are advised against prescribing opioid cough medications to patients using benzodiazepine or other CNS depressants, including alcohol, and they should only prescribe opioids with benzodiazepines or other CNS depressant medications to patients who have no adequate alternative treatment options. Prescribed combinations of opioid medicines and benzodiazepines should be limited in dosages and duration of each drug to the minimum possible.

Patients and caregivers should be warned about the drugs’ risks and seek immediate medical attention if they experience unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness while taking these medications.

The FDA is also in the process of evaluating the combined use of benzodiazepine and other CNS depressants with medication-assisted therapy drugs used to treat opioid addiction and dependence, as well as determining whether labeling revisions are necessary for other CNS depressants similar to benzodiazepines. In the meantime, the agency is urging health care professionals and patients to report any adverse effects related to these products to its MedWatch Safety Information and Adverse Event Reporting Program.

Prescription opioids (Table 1) are used to manage pain and treat cough, while benzodiazepines and other CNS depressants (Table 2) are typically used to treat anxiety, insomnia, and seizures.

Table 1: Prescription Opioid Pain and Cough Medicines

Generic Name

Found in Brand Name(s)

alfentanil

Alfenta

buprenorphine

Belbuca, Buprenex, Butrans

butorphanol

No brand name currently marketed

codeine

Fioricet w/ codeine, Fiorinal w/ codeine, Soma Compound w/ codeine, Tylenol w/ codeine, Prometh VC w/ codeine (cough), Triacin-C (cough), Tuzistra-XR (cough)

dihydrocodeine

Synalgos-DC

fentanyl

Abstral, Actiq, Duragesic, Fentora, Ionsys, Lazanda, Sublimaze, Subsys

hydrocodone

Anexsia, Hysingla ER, Lortab, Norco, Reprexain, Vicodin, Vicoprofen, Zohydro ER, Flowtuss (cough), Hycofenix (cough), Obredon (cough), Rezira (cough), Tussicaps (cough), Tussigon (cough), Tussionex Pennkinetic (cough), Vituz (cough), Zutripro (cough)

hydromorphone

Dilaudid, Dilaudid-HP, Exalgo

meperidine

Demerol

methadone

Dolophine

morphine

Astramorph PF, Duramorph PF, Embeda, Infumorph, Kadian, Morphabond, MS Contin

oxycodone

Oxaydo, Oxycet, Oxycontin, Percocet, Percodan, Roxicet, Roxicodone, Xartemis XR

oxymorphone

Opana, Opana ER

pentazocine

Talwin

remifentanil

Ultiva

sufentanil

Sufenta

tapentadol

Nucynta, Nucynta ER

tramadol

Conzip, Ultracet, Ultram, Ultram ER

Table 2: Benzodiazepines and Other CNS Depressants

Generic Name

Brand Name(s)

Benzodiazepines

alprazolam

Xanax, Xanax XR

chlordiazepoxide

Librium, Librax

clobazam

Onfi

clonazepam

Klonopin

clorazepate

Gen-Xene, Tranxene

diazepam

Diastat, Diastat Acudial, Valium

estazolam

No brand name currently marketed

flurazepam

No brand name currently marketed

lorazepam

Ativan

oxazepam

No brand name currently marketed

quazepam

Doral

temazepam

Restoril

triazolam

Halcion

Other Sleep Drugs and Tranquilizers

butabarbital sodium

Butisol

eszopiclone

Lunesta

pentobarbital

Nembutal

ramelteon

Rozerem

secobarbital sodium

Seconal sodium

suvorexant

Belsomra

zaleplon

Sonata

zolpidem

Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist

Muscle Relaxants

baclofen

Gablofen, Lioresal

carisoprodol

Soma, Soma Compound, Soma Compound w/ codeine

chlorzoxazone

No brand name currently marketed

cyclobenzaprine

Amrix

dantrolene

Dantrium, Revonto, Ryanodex

metaxalone

Skelaxin

methocarbamol

Robaxin, Robaxin-750

orphenadrine

No brand name currently marketed

tizanidine

Zanaflex

Antipsychotics

aripiprazole

Abilify, Abilify Maintena, Aristada

asenapine

Saphris

cariprazine

Vraylar

chlorpromazine

No brand name currently marketed

clozapine

Clozaril, Fazaclo ODT, Versacloz

fluphenazine

No brand name currently marketed

haloperidol

Haldol

iloperidone

Fanapt

loxapine

Adasuve

lurasidone

Latuda

molindone

No brand name currently marketed

olanzapine

Symbyax, Zyprexa, Zyprexa Relprevv, Zyprexa Zydis

paliperidone

Invega, Invega Sustenna, Invega Trinza

perphenazine

No brand name currently marketed

pimavanserin

Nuplazid

quetiapine

Seroquel, Seroquel XR

risperidone

Risperdal, Risperdal Consta

thioridazine

No brand name currently marketed

thiothixene

Navane

trifluoperazine

No brand name currently marketed

ziprasidone

Geodon

*This is not a comprehensive list.