Promethazine-Codeine Risks, Warnings, and Complications

MISUSE, ABUSE, AND ADDICTION: Codeine is an opioid and a Schedule V controlled substance. It carries a risk of misuse, abuse, and addiction, even when used at the recommended doses. Risk factors include taking the medicine without a doctor’s prescription, at higher doses, or for longer than prescribed. People with a history of substance use disorder (alcohol abuse or drug abuse) and those with mental health conditions such as major depression are at a higher risk of developing an addiction (physical and psychological dependence).

 Your doctor will carefully weigh the pros and cons of prescribing promethazine with codeine. They will prescribe this medication only when the cause of your symptoms is known. You should take the lowest effective dose of promethazine with codeine for the shortest time possible to control your common cold and allergy symptoms.

LIFE-THREATENING RESPIRATORY DEPRESSION: Codeine, one of the active ingredients in promethazine cough syrup and codeine combination, is an opioid drug. It can cause respiratory depression (dangerously slowed or shallow breathing) by acting directly on the breathing center in the central nervous system (CNS). This complication can be fatal. Breathing problems are more likely to occur in the first 24-72 hours of taking the medicine but can occur at any time during treatment. 

Risk factors that can raise the risk of severe breathing problems include taking other central nervous system depressants. Examples of other CNS depressants include alcohol, anti-anxiety drugs called benzodiazepines, sedatives, tranquilizers, and muscle relaxants. 

Other risk factors for slowed or shallow breathing include pre-existing chronic lung conditions (for example, asthma, COPD, chronic bronchitis, obstructive sleep apnea). Also, people with altered pharmacokinetics and reduced drug clearance (for example, debilitated or cachectic patients) are at an increased risk of slowed or shallow breathing.

The risk of life-threatening respiratory depression from opioids is greater in children. Promethazine and codeine is not recommended for pediatric patients under 18 years of age. It is contraindicated in children younger than 12 years of age and children of any age who have undergone tonsillectomy and adenoidectomy. To prevent potentially fatal respiratory depression, make sure you store the medicine safely out of reach of children. 

Measure the dose of liquid medicine using a dose-measuring device (cup or syringe) to prevent dosing errors or an accidental overdose. Call your doctor immediately or seek emergency medical care if you develop any difficulty breathing. 

ULTRA-RAPID METABOLIZERS: Some people are ultra-rapid metabolizers of codeine because of a specific genotype of CYP2D6. These individuals have a genetic variation that causes them to convert codeine to its active metabolite (morphine) faster than most people. This can lead to high serum morphine levels and put them at risk of respiratory depression due to a morphine overdose. Seek emergency medical care if someone develops extreme sleepiness, shallow breathing, or confusion after taking promethazine with codeine.

DROWSINESS, DIZZINESS, AND DIFFICULTY CONCENTRATING: Taking opioid medicines such as codeine can cause sleepiness, lightheadedness, and decreased mental alertness. This can be dangerous during activities like driving or operating machinery. The risk is greater if someone is taking other medications that also cause drowsiness and dizziness, such as sleep aids, sedatives, benzodiazepines, and muscle relaxants. Older adults (aged 65 years and above) are at a higher risk of these side effects. Alcohol can make these symptoms worse. Do not drive or do other potentially hazardous activities until you know how promethazine with codeine affects you.

DRUG INTERACTIONS: Taking promethazine with codeine with certain drugs or discontinuing certain drugs can increase codeine levels in the body and lead to more severe adverse effects, including potentially fatal respiratory depression. Examples of potential drug interactions with promethazine-codeine include macrolide antibiotics (erythromycin), antifungal agents (ketoconazole), HIV medicines (ritonavir), anti-tubercular drugs (rifampin), and antiepileptic drugs (phenytoin, carbamazepine). 

Other drug interactions can lead to lower codeine concentrations in the body and lead to treatment failure or opioid withdrawal symptoms in some patients. 

Additional interactions include drugs called monoamine oxidase inhibitors (MAOIs).

Give your doctor and pharmacist a complete list of all your medications, including prescription drugs, over-the-counter medications, dietary supplements, and herbal products to avoid potentially dangerous drug interactions.

RISKS IN PEOPLE WITH CERTAIN MEDICAL CONDITIONS: People with certain health conditions, such as paralytic ileus, head injury, increased intracranial pressure, brain tumors, impaired consciousness, or seizure disorders are at an increased risk of complications from taking promethazine with codeine. Give your healthcare professional a complete medical history before starting this medication.

NEUROLEPTIC MALIGNANT SYNDROME: Promethazine with codeine is linked to a potentially fatal condition called neuroleptic malignant syndrome (NMS). It can occur when on this medicine alone or with antipsychotic drugs. 

Symptoms include high fever, muscle rigidity, changes in mental status, fast pulse, irregular heartbeat, fluctuations in blood pressure, and sweating. These symptoms can resemble other serious medical illnesses like pneumonia, systemic infections, drug fever, heat stroke, untreated extrapyramidal symptoms (EPS), central anticholinergic toxicity, and primary central nervous system (CNS) conditions.

Stop taking promethazine with codeine and seek emergency medical care if you develop the above-listed symptoms.

PARADOXICAL REACTIONS INCLUDING DYSTONIA: Promethazine is a phenothiazine and can cause dystonic reactions (involuntary muscle contractions with abnormal postures and repetitive twisting movements, neck stiffness, tongue protrusion, and hyperexcitability). The risk of this occurring is particularly high in pediatric patients with an acute illness that causes dehydration. Stop the use of promethazine with codeine immediately if these symptoms develop. 

SEIZURE RISK: Promethazine with codeine can increase the risk of seizures in people with seizure disorders. Tell your doctor if you have epilepsy before starting this medicine. Call your healthcare provider if you have worsening seizure control during treatment.

BONE MARROW DEPRESSION: Caution is advised before prescribing promethazine with codeine to people with bone marrow depression. There are reports of leukopenia and agranulocytosis (low white blood cells) in patients who took promethazine, especially if they were on other drugs that are also toxic to the bone marrow.

SEVERE HYPOTENSION: Promethazine with codeine can cause hypotension (a drop in blood pressure) with symptoms such as dizziness and fainting, especially when going from a sitting or lying position to standing. Get out of bed slowly to lower the risk of falls. Tell your doctor if you take a blood pressure medication or experience dizziness or lightheadedness.

NEONATAL OPIOID WITHDRAWAL SYNDROME: Taking codeine during pregnancy can expose the unborn baby to the opioid drug and cause the baby to develop a physical dependence on opioids. After birth, the baby can experience life-threatening opioid withdrawal symptoms. This condition is called neonatal opioid withdrawal syndrome. Doctors do not usually prescribe opioids to pregnant women due to this risk. If you take codeine while you’re pregnant, especially for a prolonged time, observe your infant closely for signs of neonatal opioid withdrawal syndrome, such as high-pitched crying, poor feeding, irritability, poor sleep, and seizures.

ADRENAL INSUFFICIENCY: Codeine and other opioids, especially when taken for long periods, can lead to adrenal insufficiency (decreased adrenal hormone levels). Symptoms may include nausea, vomiting, loss of appetite, weakness, tiredness, dizziness, and low blood pressure. Tell your doctor right away if you experience these symptoms. You may need to receive corticosteroids for the treatment of adrenal insufficiency.

LABORATORY TESTS: Opioids can alter the results of certain lab tests such as liver enzymes, pregnancy tests, and glucose tolerance tests. Tell all your healthcare professionals, including laboratory personnel, that you are on promethazine with codeine before any lab tests.