Say your levothyroxine tablet goes down with water at 7 and your calcium tablet with breakfast at 7:45. By the Synthroid label, those two are more than 3 hours too close.
Some everyday supplements, including calcium, iron, magnesium and zinc, can keep certain prescription medicines from being absorbed when the two are swallowed together. The question is how far apart, and the answer lives in each drug's FDA-approved label, and the labels don't all say the same thing.
For this guide we read the current labels on DailyMed, the National Library of Medicine's database of FDA drug labeling, and every spacing number below is quoted from one of them. Generic versions of the same drug can word things slightly differently. Use this as a map of the questions to ask, and follow the label of the product you actually take.
What happens in the gut
Calcium, iron, magnesium, aluminum and zinc are metals that carry more than one positive charge, which is why drug labels call them multivalent or polyvalent cations. Some drug molecules grab on to these metals in the digestive tract, and the bound drug isn't absorbed as well.
A 1990 review in Clinical Pharmacokinetics described how tetracyclines form insoluble complex molecules by metal ion chelation with antacids, and said tetracycline absorption may fall by more than 90% as a result. In a randomized crossover study in male volunteers (the abstract doesn't give the number), taking 400 mg of ciprofloxacin together with 1,200 mg of calcium polycarbophil lowered the amount of ciprofloxacin in the blood over 12 hours by about 50%, which the authors attributed to the formation of chelate complexes. Separating the doses in time is how most of the labels handle it.
What each label says
Levothyroxine
Back to the breakfast table. The Synthroid label says to take the tablet "on an empty stomach, one-half to one hour before breakfast" and "at least 4 hours before or after drugs known to interfere with SYNTHROID absorption." Its interaction table names calcium carbonate and ferrous sulfate (a form of iron), listed there as examples of phosphate binders, with the instruction "Administer SYNTHROID at least 4 hours apart from these agents." In the patient counseling section, prescribers are told to instruct patients "not to take SYNTHROID tablets within 4 hours" of iron supplements, calcium supplements and antacids.
For antacids such as aluminum and magnesium hydroxides, the same table gives a different reason: "Gastric acidity is an essential requirement for adequate absorption of levothyroxine." There the table says to "Monitor patients appropriately," while the patient instructions still put antacids inside the 4-hour rule.
The Levoxyl label gives the same 4-hour spacing for calcium carbonate and ferrous sulfate, and spells out the chemistry: "Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex." More on these pairs: levothyroxine and calcium and levothyroxine and iron.
Food counts too. The Synthroid label says "Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of SYNTHROID," and that "Grapefruit juice may delay the absorption of levothyroxine." It sets no fixed gap for these foods. It tells prescribers to evaluate the need for a dose adjustment when the tablet is regularly taken within one hour of certain foods.
Tetracycline and doxycycline
A current tetracycline capsule label says absorption "is impaired by antacids containing aluminum, calcium or magnesium and preparations containing iron, zinc or sodium bicarbonate," and adds: "Food and some dairy products also interfere with absorption." It doesn't give a number of hours (see tetracycline and zinc).
Doxycycline labels name a similar list: the Doryx MPC label says absorption of tetracyclines "is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations." On food, doxycycline differs. A generic doxycycline hyclate label notes that tetracyclines in general are absorbed less with foods, "especially those which contain calcium," but says doxycycline's absorption "is not markedly influenced by simultaneous ingestion of food or milk," and recommends taking it with food or milk if it irritates the stomach.
Neither doxycycline label we read states an interval in hours.
When a label names what interferes but not how long to wait, that's the question I'd bring to the pharmacist at pickup, especially if you take a daily multivitamin, calcium or iron (see doxycycline and calcium).
Ciprofloxacin and levofloxacin
The fluoroquinolone labels do give numbers, and the two we read differ.
A current generic ciprofloxacin label says to "Administer ciprofloxacin at least 2 hours before or 6 hours after" magnesium or aluminum antacids, sucralfate, phosphate binders, some buffered drugs "or other products containing calcium, iron or zinc." It notes that antacids containing magnesium hydroxide or aluminum hydroxide "may reduce the bioavailability of ciprofloxacin by as much as 90%." Dairy gets its own rule: avoid taking ciprofloxacin with dairy products "(like milk or yogurt) or calcium-fortified juices alone," although it "may be taken with a meal that contains these products." The same label says ciprofloxacin "may increase the effects of caffeine" (see coffee and ciprofloxacin).
A current generic levofloxacin label sets a shorter window. The tablets "should be administered at least two hours before or two hours after" magnesium or aluminum antacids, sucralfate, "metal cations such as iron, and multivitamin preparations with zinc." The label adds that chelation by divalent cations "is less marked than with other fluoroquinolones."
So a multivitamin taken first can mean a 6-hour wait before a ciprofloxacin dose but only a 2-hour wait before levofloxacin. Same multivitamin, four hours' difference.
Alendronate and risedronate
Oral bisphosphonates for osteoporosis are barely absorbed even under ideal conditions. The Fosamax label puts the mean oral bioavailability of alendronate in women at 0.64% when taken after an overnight fast, two hours before breakfast. Hence the strict rules.
Alendronate (Fosamax). Take it "at least one-half hour before the first food, beverage, or medication of the day with plain water only." The label says other beverages, mineral water included, are likely to reduce absorption. It states that calcium, antacids and oral medicines containing multivalent cations "will interfere with absorption" and tells patients "to wait at least one-half hour after taking FOSAMAX before taking any other oral medications." Coffee gets a number: taking alendronate with coffee or orange juice "reduced bioavailability by approximately 60%" (see alendronate and coffee). Patients also shouldn't lie down for at least 30 minutes and until after their first food of the day.
Risedronate (Actonel). The Actonel label says to take it "at least 30 minutes before the first food or drink of the day other than water," and before any supplement. It goes further than Fosamax, telling patients to take "calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day."
Delayed-release risedronate (Atelvia). This version flips the breakfast rule: the Atelvia label says it "should be taken immediately following breakfast and not under fasting conditions." Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations still "should not be taken together" with it, and the label says to take them "at a different time of the day." In a single-dose crossover study in 101 postmenopausal women, a tablet with 600 mg of elemental calcium and 400 IU of vitamin D taken with Atelvia after breakfast reduced risedronate absorption by approximately 38%.
Two forms of the same drug, opposite instructions about breakfast. That alone is reason to follow the label of your own product.
Dolutegravir
The HIV medicine dolutegravir shows how food can change the rule. The Tivicay label says to take it "2 hours before or 6 hours after" medicines containing polyvalent cations, such as antacids or laxatives with aluminum or magnesium, sucralfate and buffered medicines. For calcium or iron supplements, including multivitamins that contain them, the label says: "When taken with food, TIVICAY and supplements or multivitamins containing calcium or iron can be taken at the same time." Under fasting conditions, the 2-hours-before or 6-hours-after rule applies to those supplements too.
Combination pills that contain dolutegravir carry their own instructions. The Juluca label (dolutegravir with rilpivirine) says to take it "4 hours before or 6 hours after taking antacids," and the same gap applies to calcium or iron supplements unless the two are taken "together with a meal."
Quick reference
A summary of the labels we read, not a schedule: your own product's label and your pharmacist come first.
- Levothyroxine (Synthroid, Levoxyl): calcium, iron and antacids at least 4 hours apart, before or after.
- Tetracycline: aluminum, calcium or magnesium antacids, iron, zinc, food and some dairy interfere. No hour count in the label we read; ask your pharmacist.
- Doxycycline: aluminum, calcium or magnesium antacids, bismuth subsalicylate and iron interfere. One generic label says food and milk do not markedly affect doxycycline absorption. No hour count in the labels we read.
- Ciprofloxacin: at least 2 hours before or 6 hours after products with calcium, iron, zinc, magnesium or aluminum. Not with milk, yogurt or calcium-fortified juice alone.
- Levofloxacin: at least 2 hours before or 2 hours after magnesium or aluminum antacids, iron and multivitamins with zinc.
- Alendronate (Fosamax): plain water only, at least 30 minutes before food, drinks (coffee included) and other medicines.
- Risedronate (Actonel): at least 30 minutes before food, drinks other than water, and supplements. Calcium, magnesium, iron and antacids at a different time of day.
- Risedronate delayed-release (Atelvia): right after breakfast. Calcium, magnesium, iron and antacids at a different time of day.
- Dolutegravir (Tivicay): 2 hours before or 6 hours after aluminum or magnesium antacids and laxatives. Calcium or iron supplements can be taken at the same time if Tivicay is taken with food; without food, the same 2-hour or 6-hour gap applies. Combination pills such as Juluca have different numbers.
Before you change anything
Don't move the time you take a prescription medicine on your own. Some of these drugs leave little room for error: the Synthroid label notes that levothyroxine "has a narrow therapeutic index." Your pharmacist can review everything you take, prescription and over the counter, and build a daily schedule that keeps the right gaps.
If you take a multivitamin, I'd mention it by name, since several of these labels single out multivitamins that contain calcium, iron or zinc. And if your prescriber has given you instructions that differ from the label, follow your prescriber and ask them about it.
In Pilora you can schedule each supplement at a set time apart from your medicines, with a reminder at each time.
The bottom line
The gaps in the labels range from 30 minutes to 6 hours, and some labels give no number at all. That's too much variety to guess at: follow the label of your specific product, and ask your pharmacist or prescriber to set the timing before you change your routine.