Promethazine: Medical Uses, Side Effects, Pharmacology, History, Administration and Warnings

It is a first-generation neuroleptic and antihistamine drug from the phenothiazine family. The drug has strong sedative antipsychotic effects.

It also reduces motion sickness and has antiemetic (Histamine H1 receptors but does not block histamine production) and anticholinergic properties. In some countries, it is prescribed for insomnia when benzodiazepines are contraindicated.

Promethazine was developed in the mid-1940s when a team of scientists at the Rhône-Poulenc laboratories synthesized it from phenothiazine and a diphenhydramine side chain of diamine.

How Promethazine Works

This drug belongs to two classes of medications called antihistamines and antiemetics. A type of drug is a group of drugs that work similarly. These drugs are often used to treat similar conditions.

Promethazine works by preventing the release of a histamine substance from specific cells in your body. Histamine is usually released when exposed to things you are allergic to, such as pollen, dander, mold, or chemicals.

This drug causes drowsiness and helps control pain by preventing the release of histamine. This is because histamine helps regulate wakefulness and helps you stay alert, and heightens your senses.

This drug also works to reduce the stimulation of the part of your brain that sends signals to make you vomit.


Medical uses

Promethazine is used to relieve symptoms of other allergic reactions such as the runny nose and watery eyes caused by allergy to pollen, mold, or dust, allergic conjunctivitis, allergic skin reactions, and allergic reactions to plasma products.

Promethazine is used for several reasons, including to treat allergies, motion sickness, nausea and vomiting, anxiety before surgery, and pain after surgery. It is also used as a sleep aid, even before and after surgery.

This medicine can be used as part of combination therapy. This means that you may need to take it with other medications.

Promethazine is used together with other medications to treat anaphylaxis, sudden and severe allergic reactions, and symptoms of the common cold, such as sneezing, coughing, and runny nose.

As an adjunct treatment for anaphylactoid conditions (intramuscular injection or intravenous therapy is preferred). As a motion sickness or motion sickness remedy when used with ephedrine or pseudoephedrine.

It is also used to treat migraines; however, other similar drugs, such as Compazine, have been shown to have a more favorable treatment profile and are used almost exclusively over promethazine.

Promethazine side effects

Some documented side effects include:

  • Tardive dyskinesia (effects due to dopamine D2 receptor antagonism).
  • Akathisia (the inability to stay still).
  • Paresthesia.
  • Short temper/irritability.
  • Drowsiness.
  • Changes in blood pressure
  • Allergic skin reactions.
  • Low platelet counts.
  • Reduction in the production of white blood cells.
  • Respiratory problems.
  • Increased excitability.
  • Abnormal movements

If these effects are mild, they can go away in a few days to a couple of weeks. If they are more severe or do not go away, talk to your doctor or pharmacist.

Call your doctor right away if you have serious side effects. Call 911 if your symptoms seem life-threatening or think you have a medical emergency. Serious or infrequent side effects and their symptoms may include the following:

Extrapyramidal symptoms (uncontrollable movements). Symptoms can include:

  • Disobedient upward gaze and twitching of the eyes and eyelids.
  • Uncontrollable contractions of the neck muscles cause your head to twist or turn to the side.
  • Seizures
  • Hallucinations (seeing things that are not there).

Abnormal heart rhythm Symptoms can include:

  • Palpitations
  • Dizziness.
  • Fainting.
  • Difficulty breathing.
  • Chest pain.

Decreased production of platelets and white blood cells. Symptoms can include:

  • Bruising or abnormal bleeding: This includes bleeding from minor cuts, bleeding from the nose or mouth, and red patches on the skin. It also includes abnormally heavy menstrual flow, blood in the urine, or black tarry stools.
  • Fevers or infections.
  • Severe breathing problems

Angioedema (accumulation of fluid deep in the skin or under the skin). Symptoms can include:

  • Swelling is usually around the eyes, lips, and sometimes the throat, hands, and feet.
  • Spraying on the surface of the skin (welts).
  • Itchy bumps and pains ( hives ).

Neuroleptic malignant syndrome (a reaction to antipsychotic drugs that is sometimes fatal). Symptoms can include:

  • Fever.
  • Muscular stiffness.
  • Mental changes
  • Changes in pulse or blood pressure.
  • Fast heart rate
  • Increased sweating
  • Irregular heartbeat

Jaundice. Symptoms can include:

  • Yellow skin.
  • Yellowing of the whites of your eyes.
  • Dark or brown urine.
  • Yellowing of the inside of your mouth.
  • Pale or clay-colored stools

Promethazine is listed as one of the drugs with the highest anticholinergic activity in an anticholinergic load study, including long-term cognitive decline.

Extreme Drowsiness warning: This drug may cause excessive drowsiness. Do not drive a car or use machinery until you know how this drug affects you.

Neuroleptic Malignant Syndrome Warning: The use of this drug is associated with Neuroleptic Malignant Syndrome. This condition can be fatal.

Symptoms may include fever, stiff muscles, mental changes, pulse or blood pressure changes, fast heartbeat, increased sweating, or irregular heartbeat.

Promethazine and children

Promethazine can cause breathing to slow or stop and cause death in children. Promethazine should not be given to infants or children under two years of age and should be administered with caution to children two years of age or older.

Promethazine should not be used routinely to treat vomiting in children; it should only be used in specific cases when a doctor decides it is necessary.

Tell your doctor or pharmacist about all your child’s medicines, especially barbiturates such as phenobarbital (Luminal), anxiety medicines, narcotic pain medicines, sedatives, sleeping pills, and tranquilizers.

Call your child’s doctor right away and get emergency medical treatment if your child has trouble breathing, wheezes, slows or pauses in breathing, or stops breathing.


Promethazine, a derivative of phenothiazine, is structurally different from neuroleptic phenothiazines, with similar but different effects.

It acts primarily as a potent H1 receptor antagonist (antihistamine) and a moderate Mach receptor antagonist (anticholinergic). Also, it has a weak to moderate affinity for 5-HT2A, 5-HT2C, D2, and α1-adrenergic receptors, where it also acts as an antagonist at all sites.

Promethazine is another notable use as a local anesthetic by blocking sodium channels.

This drug has a black box warning. This is the most severe warning from the Food and Drug Administration. A black box warning alerts doctors and patients to potentially dangerous drug effects.

Promethazine is a prescription drug. It is available as an oral solution, a rectal suppository, and an oral tablet.

The oral tablet is only available as a generic drug. Generic drugs generally cost less than brand-name versions.

Promethazine Chemical Properties

Solid Promethazine Hydrochloride is a white to pale yellow crystalline powder that is practically odorless. Slow oxidation can occur with prolonged exposure to air, usually causing blue discoloration.

Its hydrochloride salt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound that occurs as a mixture of enantiomers.


A group first synthesized promethazine at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the early 1940s. The team sought to improve diphenhydramine; the same line in medical chemistry led to the creation of chlorpromazine.

Product liability lawsuit

In 2009, the US Supreme Court ruled on a product liability case related to promethazine. Diana Levine, a woman, suffering from migraine headaches, received Wyeth’s Phenergan through intravenous therapy.

The drug was injected incorrectly, resulting in gangrene and subsequent amputation of his right forearm below the elbow. A state jury awarded him $ 6 million in punitive damages.

The case was appealed to the Supreme Court for federal preference and due process of law. The Supreme Court upheld the lower court rulings. It stated that “Wyeth could have unilaterally added a stronger warning about the IV-push administration” without acting in opposition to federal law.

This means that drug manufacturers can be held liable for injuries if state courts deem the warnings of potential adverse effects, approved by the US Food and Drug Administration (FDA), insufficient.

On September 9, 2009, the FDA required a boxed warning on Promethazine for Injection, setting out the contraindication for subcutaneous administration. The preferred route of administration is intramuscular, which reduces the risk of surrounding muscle and tissue damage.


On longer trips, promethazine is usually taken in the morning and before dinner on each day of travel.

Promethazine can also be taken at bedtime the night before surgery to relieve anxiety and produce a peaceful sleep. Take promethazine exactly as directed. Promethazine suppositories are for rectal use only.

To insert a promethazine suppository, follow these steps:

If the suppository feels soft, keep it under cold water for 1 minute. Remove the wrap. Keep it in place for a few moments.

What special precautions should I follow?

Tell your doctor if you have or have ever had an enlarged prostate (a male reproductive gland); or glaucoma (a condition in which increased pressure in the eye can lead to gradual loss of vision).

Interactions with other medications

Promethazine can interact with other medications.

Oral promethazine can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

Examples of medications that can cause interactions with promethazine are listed below:

Allergy Drugs

When you take certain allergy medications with promethazine, you may have increased side effects. These can include dry mouth, constipation, trouble emptying the bladder, blurred vision, and drowsiness. Examples of these medications include:

  • Brompheniramine.
  • Carbinoxamine.
  • Chlorpheniramine.
  • Clemastine.
  • Cyproheptadine.
  • Difenhidramina.
  • Hydroxyzine.

Antidepressant drugs

Taking certain antidepressant medications called monoamine oxidase inhibitors (MAOIs) with promethazine increases the risk of extrapyramidal symptoms.

These symptoms include an uncontrollable upward gaze, twitching of the eyes and eyelids, uncontrollable contractions of the neck muscle (causing the head to twist or turn to the side), and sticking out the tongue uncontrollably. Examples of these medications include:

  • Isocarboxazid.
  • Phenelzine.
  • Tranylcypromine.

When you take medicines called tricyclic antidepressants with promethazine, you may have more extreme drowsiness and last longer. Examples of these medications include:

  • Amitriptyline.
  • Amoxapine.
  • Clomipramine.
  • Desipramine.
  • Doxepin.
  • Imipramine.
  • Nortriptyline.
  • Protriptyline.
  • Trimipramine.

Drugs for anxiety

When you take certain anxiety medications with promethazine, you may have drowsiness that is more extreme and lasts longer. Examples of these medications include:

  • Brompheniramine.
  • Carbinoxamine.
  • Chlorpheniramine.
  • Clemastine.
  • Cyproheptadine.
  • Difenhidramina.
  • Hydroxyzine.

Medications for bladder control

Specific side effects can increase and last longer when you take certain bladder control medications with promethazine.

These side effects include dry mouth, constipation, trouble emptying the bladder, blurred vision, and drowsiness. Examples of these medications include:

  • Darifenacin.
  • Flavoxate.
  • Oxibutinina.
  • Solifenacin.
  • Tolterodine.
  • Prospero.

Muscle relaxants

When you take certain muscle relaxants with promethazine, you may have more extreme drowsiness, lasting longer. Examples of these medications include:

  • Baclofen.
  • Carisoprodol.
  • Chlorzoxazone.
  • Cyclobenzaprine.
  • Dantrolene.
  • Metaxalone.
  • Methocarbamol.
  • Orphanage.
  • Tizanidine.

Drugs for nausea and motion sickness

When you take certain drugs for nausea and motion sickness with promethazine, specific side effects can increase and last longer.

These side effects include dry mouth, constipation, trouble emptying the bladder, blurred vision, and drowsiness. Examples of these medications include:

  • Dimenhydrinate.
  • Meclizine.
  • Scope.

Pain drugs

When you take certain pain relievers with promethazine, you may have drowsiness that is more extreme and lasts longer. Examples of these medications include:

  • Codeine.
  • Fentanyl.
  • Hydrocodone.
  • Hydromorphone.
  • Levorphanol.
  • Meperidine.
  • Methadone.
  • Morphine.
  • Oxycodone.
  • Oxymorphone.
  • Tramadol.

Medications for Parkinson’s disease

Some side effects can increase and last longer when you take certain Parkinson’s disease medications with promethazine. These side effects include dry mouth, constipation, trouble emptying the bladder, blurred vision, and drowsiness. Examples of these medications include:

  • Benztropine.
  • Trihexifenidilo.
  • Amantadine.

convulsive drug

Taking phenobarbital with promethazine can lower the levels of promethazine in your body. Promethazine may not work well at this reduced level.

Sleep medications

When you take certain promethazine sleep medications, you may have drowsiness that is more extreme and lasts longer. Examples of these medications include:

  • Chloral Hydrate.
  • Estazolam.
  • Eszopiclone.
  • Flurazepam.
  • Temazepam.
  • Triazolam.
  • Zaleplon.
  • Zolpidem.

Gastrointestinal drugs

Certain side effects can increase and last longer when you take certain stomach and gastrointestinal medications with promethazine.

These side effects include dry mouth, constipation, trouble emptying the bladder, blurred vision, and drowsiness. Examples of these medications include:

  • Belladonna/phenobarbital alkaloids.
  • Chlordiazepoxide/clinidium.
  • Dicyclomine.
  • Glycopyrrolate.
  • Hyoscyamine.
  • Methscopolamine.
  • Scopolamine.

Promethazine warnings

This drug comes with several warnings.

Allergy warning

This medicine can cause a severe allergic reaction. Symptoms can include:

  • Difficulty breathing.
  • Swelling of your throat or tongue.

Call 911 or go to the nearest emergency room if you develop these symptoms.

Do not retake this medicine if you have ever had an allergic reaction. Retaking it could be fatal (cause death).

Interaction with alcohol

Drinking alcohol can make the drowsiness from promethazine more extreme and last longer. To avoid this, do not drink alcohol while taking this medicine.

Warnings for people with certain health conditions

Angle-closure glaucoma leads to increased pressure in your eyes for people with angle-closure glaucoma. If you have a history of angle-closure glaucoma, taking this drug can cause a sudden and severe increase in pressure in the eye.

This is an emergency and can lead to irreversible vision loss. Talk to your doctor before using this medicine if you have this condition.

For people with an enlarged prostate: If you have trouble urinating due to an enlarged prostate gland, taking this drug may make it even more difficult to urinate.

For people with specific stomach problems: If you have a history of digestive tract obstruction, taking this drug may worsen the blockage. This is because this drug slows down movement through your digestive tract.

For people with specific bladder problems: If you have a blockage in your bladder, taking this drug can make urination difficult. This is because it narrows the tubes through which urine flows.

For people with bone marrow disease: This drug lowers the levels of platelets and white blood cells. You should not take it if you have bone marrow disease or take other medications that affect the bone marrow’s ability to make blood cells.

For people with heart disease: If you have heart disease, taking this drug can make it worse. This medicine can cause your heart rhythm to be abnormal.

For people with liver disease: When your body removes this drug, it first breaks it down in your liver. If you have liver disease, your liver cannot break down the medicine as fast as possible.

This means that the level of this drug in your body could become too high. This increases the risk of side effects.

For people with breathing problems: This medicine can thicken the secretions in the breathing tubes.

If you have asthma or chronic obstructive pulmonary disease (COPD), this can cause an asthma attack or worsen your chronic obstructive pulmonary disease. The drug should not be taken during an acute asthma attack or if you have chronic obstructive pulmonary disease.

For people with sleep apnea: This medicine can thicken the secretions in the breathing tubes. If you have sleep apnea, taking this drug at night can worsen your condition.

For people with seizures: This drug increases the risk of having seizures. Consult your doctor if you take other medications that can cause seizures. Taking these medications together can increase this risk.

Warnings for other groups

For pregnant women: Promethazine is a category C pregnancy drug. That means two things:

  • Research in animals has shown adverse effects on the fetus when the mother takes the drug.
  • Not enough human studies have been done to determine how the drug might affect the fetus.

Talk to your doctor if you are pregnant or planning to become pregnant. This drug should be used only if the potential benefit justifies the potential risk to the fetus.

This medicine should not be given to a pregnant woman within two weeks after delivery because it increases the risk of bleeding.

For breastfeeding women: Promethazine can pass into breast milk and may cause side effects in a child who is breastfed. Talk to your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this medicine.

For seniors: Older people may be more sensitive to the sedative effects of this drug. They may be more likely to experience severe drowsiness, decreased mental alertness, and confusion.

This medicine should not be used in children under two years of age. In children this age, this medicine can cause slow breathing that could be fatal. Caution should also be exercised when administering this drug to children older than two years.

This medicine should not be used in children taking other drugs that can cause slow breathing. High and excessive doses of this medicine in children can cause sudden death.

This medicine is not recommended for treating uncomplicated vomiting in children. It should only be used during prolonged periods of vomiting when the cause is known.

Some children who have taken this medicine at the recommended doses have had hallucinations and seizures. If children have a temporary illness, such as a cold or the flu, and take this drug, their risk of involuntary muscle contractions increases.