All medications have the potential to cause unwanted effects such as nausea, dizziness, stomach upset, rashes, and other issues. These adverse effects can be caused by drug allergy or by drug intolerance. Pills contain ingredients that are supposed to improve a medication’s taste, colour, absorption, or shelf life. Some of these chemicals are allergenic and can cause allergic reactions. Active ingredients of a drug exert substantial changes in your body’s function, making it challenging to understand whether side effects are due to a drug allergy or drug intolerance. Drug intolerance, or drug sensitivity, is not an allergic reaction as it does not involve the immune system. Here we explain the differences between a drug allergy and drug intolerance.

Drug intolerance = side effects

Drug intolerance is mainly caused by reduced drug clearance through your body, leading to side effects. Reduced clearance can be due to poor liver or kidney function. It can also be caused by inherited genetic variations in specific liver enzyme genes that affect drug metabolism. If drug metabolism is slow, the medication can build up in the body and cause side effects.

A drug allergy is an immune response triggered by either active or inactive drug ingredients that produce a substance that causes allergic reactions. Basically, it means that your body sees something in the medication as harmful and triggers an immune response to defend against it. Milder drug allergies often manifest in symptoms such as hives, rash or fever. Severe drug allergies can also lead to a life-threatening condition called anaphylaxis, a type of shock that affects multiple body systems leading to rapid swelling, constriction of airways, and kidney damage.

Severe drug allergies

Stevens-Johnson Syndrome (SJS) is a rare but very severe immune reaction to a medication or an infection that affects skin and mucus membranes. In its most severe form, it is called toxic epidermal necrolysis (TEN). Some medications are known to trigger SJS, such as the gout medication allopurinol, antiepileptic medications (carbamazepine, lamotrigine, phenytoin), HIV drugs (abacavir, nevirapine), anti-inflammatory drugs (meloxicam and piroxicam), and sulfa-containing antibiotics and medications (sulfamethoxazole, sulfasalazine).

Some people with particular genetic variations are at higher risk of developing SJS and TEN, for example, Asians and Native North Americans. Clinical pharmacogenetic guidelines recommend genetic testing prior to prescribing medications that can trigger SJS. The testing for these genes, known as HLA genes, is covered by the Canadian healthcare system.

Severe allergic reactions are relatively rare, but many people react to inactive drug ingredients such as food dyes, complex sugars such as lactose, and peanut oil, which can cause an allergic reaction or gastrointestinal upset. A recent study found that 93% of all oral medications contain at least one inactive ingredient that could trigger an allergic reaction. The study also showed that:

• On average, a pill contains about nine inactive ingredients.
• Only 12% of drug formulations did not contain inactive ingredients
• 45% of medications contain lactose while up to 75% of adults have lactose intolerance
• Over 30% of drugs contain Yellow 5 dye (tartrazine) that can trigger allergic reactions, especially in asthma patients or with allergies
• Two-thirds of valproic capsules and all progesterone formulations contain peanut oil, which can be fatal for people with peanut allergies

People suffering from irritable bowel syndrome (IBS) and other digestive disorders are sensitive to fermentable oligosaccharides, disaccharides, and monosaccharides (FODMAP) that are present in some foods. However, 55% of oral medications contain at least one FODMAP sugar, and a few include two or more sugar types. Lactose is the most common FODMAP sugar found in medicines. Some older adults may take ten or more medications every day, and the amount of unknowingly ingested lactose is quite significant for lactose intolerant patients. The same medicine from a different manufacturer can have a different mix of inactive ingredients, and this might be one of the reasons why some people are more sensitive to generic drugs vs branded. If you have lactose intolerance or peanut allergies, please consult with your pharmacist to check the inactive components of the medications you are taking, and see which brands are safer for you.

Symptoms and drug interactions

Drug intolerance and drug sensitivity can both manifest in multiple forms including dizziness, nausea, headaches, and muscle or joint pain. Unlike drug allergies that usually manifest within a few minutes or hours after drug intake, drug intolerance typically develops over a few days or weeks. When a person’s body cannot process a drug due to the inability to properly metabolize or clear the drug from the system, drug buildup in the bloodstream increases with each subsequent drug dose. Eventually, drug concentrations reach toxic dose levels and can lead to severe side effects, liver or kidney failure, and even death. Typical side effects vary depending on the specific medication.

Drug-drug interactions occur when the same enzyme metabolizes two or more medications, and such competition causes reduced clearance of both drugs. People with an inherently reduced drug metabolism are at a higher risk of adverse effects caused by drug-drug interactions. For poor metabolizers, the use of a single drug poses an even higher risk. Known drug-gene interactions are well documented and over 170 drugs have alerts on FDA drug labels.

Pharmacogenetic tests such as Pillcheck can help patients and their healthcare providers understand whether an adverse reaction to a drug is caused by reduced drug metabolism or caused by an immune response/allergic reaction to one of the pill’s components. If you or one of your family members is ‘sensitive’ to multiple medications, consider getting Pillcheck as a personalized prescription guide.

Reker D., et al., “Inactive” ingredients in oral medications Science Translational Medicine 13 Mar 2019: Vol. 11, Issue 483, eaau6753 DOI: 10.1126/scitranslmed.aau6753

Guengerich, P.F. Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development Drug Metab Pharmacokinet. 2011; 26(1): 3–14.

Miliszewski MA at al., Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Analysis of Triggers and Implications for Improving Prevention. Am J Med. 2016 Nov;129(11):1221-1225. doi: 10.1016/j.amjmed.2016.03.022. Epub 2016 Apr 15.

Ulrich M.Zanger and Matthias Schwab Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation Pharmacology and Therapeutics Volume 138, Issue 1, April 2013, Pages 103-141