The generic version of antihistamine Phenergan, Promethazine is used for treating allergic reactions and sedating women during labor and before and after surgery. But it has been linked to numerous side effects, including fatal respiratory depression in children and gangrene.
Promethazine, an antihistamine initially developed in France in the 1940s, was approved for the U.S. in 1951. The drug is not only used in the treatment of allergic reactions, such as hay fever, but it can also be used as a sedative, to prevent motion sickness, and to combat nausea and vomiting (including morning sickness).
A year after it entered the U.S. market, a combination drug of promethazine hydrochloride and codeine (a prescription narcotic) was introduced for common-cold symptoms and cough. However the substance has also been misused as a potentially dangerous illegal street drug called “drank.”
Along with its liquid form, promethazine can be administered orally as a tablet, through the rectum as a suppository and intravenously by injection. But injection problems have linked the drug to severe tissue injuries, including gangrene.
This prompted a black box warning (the most serious drug labeling warning) from the U.S. Food and Drug Administration in late 2009. This was the second black box warning for the antihistamine drug, with the first being required in 2006 after the FDA received reports of fatal respiratory depression (inadequate ventilation or increased concentrations of carbon dioxide) in children.
These severe, potentially life-threatening conditions are in addition to the long list of side effects, both common and serious, linked to promethazine, which still remains in popular demand, with the FDA reporting a drug shortage as recent as March 2017.
Promethazine can relieve symptoms of allergic reactions, when used as an antihistamine.
It can also be used in combination with other medications, such as epinephrine, to treat anaphylaxis (a sudden, severe allergic reaction) once the condition is controlled, as well as symptoms of the common cold, such as sneezing, cough and runny nose.
Although primarily used to treat allergies, Promethazine is indicated to treat a variety of other conditions as well.
Promethazine, an antipsychotic, is used as a histamine-receptor blocker. Histamine receptors are proteins that bind with histamine to produce allergic reactions. This makes promethazine an effective antihistamine. The drug also blocks acetylcholine receptors, making it useful to prevent and treat nausea and morning sickness. Promethazine can only help control symptoms. It isn’t effective in treating the cause of symptoms or in speeding recovery, according to the National Institutes of Health (NIH).
Promethazine can cause many different side effects, some common and some serious. These side effects can affect several different body systems and organs including the brain, heart, skin, blood, stomach and intestines and lungs.
The two most serious side effects of the antihistamine medication are addressed in a boxed warning on the drug’s labeling. These reactions include respiratory depression, which can be fatal, occurring primarily in children under the age of 2, and severe tissue damage, including gangrene (a dangerous, potentially fatal condition that involves the loss of blood flow to a large area of tissue, causing it to break down and die), primarily associated injection problems.
Promethazine hydrochloride-containing products administered by injection contain two black box warnings. This is the most serious type of warning issued by the FDA for drugs and medical devices, meaning that the side effects can cause serious injury and possibly death.
The first black box warning for promethazine was added in late 2004. Promethazine is widely used in children as an antihistamine and a sedative, as well as in the treatment of nausea and vomiting. But serious and even deadly adverse events, including respiratory depression, oversedation, agitation, hallucinations, seizures, and dystonic reactions, have been reported in children, according to the New England Journal of Medicine (NEJM).
In 1995, the American Academy of Pediatrics took steps to discourage the use of promethazine in combination with other drugs and as an anesthetic premedication in children. But it wasn’t enough, as told by NEJM, and in 2000, the warnings section of the label was strengthened to recommend that promethazine not be used in children younger than 2, and that it be used with caution in older children. But despite the labeling efforts, the FDA continued to receive adverse event reports, some about fatal respiratory depression in young children.
A 2004 review of serious adverse event reports submitted to the FDA between 1969 and 2003, showed a total of 125 patients with 38 cases of respiratory depression or cardiac arrest, as published by NEJM.
Of those 38 cases, 22 involved patients aged 18 months to 2 years of age, and 7 resulted in death. Serious outcomes, including death, disability, life-threatening events, and hospitalization, occurred with all routes of administration, whether oral, rectal or intravenous injection.
“The unpredictable nature of adverse events and their serious outcomes justified further strengthening of warnings and contraindications and the addition of a boxed warning for the use of promethazine in children.”
The black box warning now clearly reads that promethazine hydrochloride injections should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression. It also advises caution should be exercised when administering the drug in the form of an injection to patients 2 and older.
In 2006, an FDA alert advised all health care professionals that the warning extended to promethazine hydrochloride (including brand name Phenergan and generic versions of the drug) in any form, whether syrups, suppositories, tablets or injectables.
In 2009, the FDA required a second black box warning for promethazine hydrochloride injection to warn patients of the risks of severe tissue injury, including gangrene, associated with the administration of the drug.
The FDA advised manufacturers to include in the black box warning that the preferred route of intravenous administration is deep intramuscular injection (directly into a muscle) and not subcutaneous injection (into the layer of skin directly below the dermis and epidermis).
The misuse of a liquid combination of promethazine hydrochloride and codeine (a narcotic pain reliever), indicated to treat common cold symptoms and cough, has become “increasingly popular among youth in several areas of the country,” according to the National Institute on Drug Abuse.
The prescription cough syrup has been known to sell on the streets for upwards of $1,000, with one brand (that the company stopped distributing in 2014) selling for as much as $3,000, Bloomberg said in 2017.
“It’s the caviar of drugs,” said Ronald Peters, a retired professor of behavioral sciences at the University of Texas Health Science Center in Houston.
It was reported that promethazine codeine syrup was prescribed about 4 million times in the U.S. in 2016, bringing in about $15 million in sales. Where it’s selling on the streets, the popular syrup is known as “purple drank,” or simply “drank.”
The U.S. Department of Health and Human Services reported that 11,000 emergency room visits occurred in the United States in 2011 (the most recent year for which data is available) as the result of codeine misuse. But even with the FDA newly scrutinizing codeine since 2013, and requiring adjusted drug labeling warnings about risks to children, the agency has not yet addressed the dangers associated with recreational use of promethazine codeine syrups, according to Bloomberg.
According to one press officer for the FDA, Sarah Peddicord, “The agency is currently evaluating all available information (latest safety data) to determine whether additional communication and/or regulatory action is needed.”
Promethazine can be administered by mouth in tablet or syrup (liquid) form, by injection (intravenously), or into the rectum in the form of a suppository. When taking liquid promethazine, patients should use a measuring spoon or cup made specifically for measuring medications, and not a household spoon. The suppository can only be inserted through the rectum (lower part of the large intestine through the anus), and should not be swallowed.
Prior to removing the wrapper, if a suppository feels soft, the patient should first hold under cold, running water for one minute. After removing the wrapper, the tip of the suppository should be dipped in water prior to insertion, using the finger. In adults, the suppository should be inserted into the rectum by one inch and by about one-half to one inch in children 2 and older.
Since promethazine HCI administered intravenously (by injection) can cause severe chemical irritation and damage to tissues, deep intramuscular injection (a technique administering medication deep into the muscles) is the preferred method of injection. Promethazine hydrochloride injections should not be given by intra-arterial (within an artery) injection, under any circumstances, due to the risk of severe arteriospasm (spasm in an artery) and resulting gangrene.
Subcutaneous (the layer of skin directly below the dermis and epidermis – true skin) injection is also not advised as it may result in tissue necrosis (death of a body tissue when there is not enough blood flow to the tissue).
Dosing for patients taking promethazine may vary based on the condition being treated, a patient’s age and weight, other medications that a patient may be taking and other medical conditions that they may have.
Promethazine can potentially interact with a number of other medications. Taking promethazine with certain medications can decrease the effectiveness of either drug or increase a patient’s risk of unwanted side effects.
Please seek the advice of a medical professional before making health care decisions.
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