Lactose Content of Typical Medication Regimens of Ambulatory Elderly Patients

Mona Gold Tsoukleris Jennifer T. Tam Dee A. Knapp

Design: 100 randomly selected profiles were retrospectively evaluated from the 533 submitted to the outpatient pharmacy between January 31 and February 4, 1994.

Setting: Inner-city Veterans Affairs Medical Center

Patients: Elderly patients age 60 and over receiving at least one oral medication.

Outcomes Measured: Lactose content was determined via telephone call to product manufacturers. Total daily lactose exposure was calculated from the prescribed regimen.

Results: A total of 100 patients with a mean (± S.D.) age of 68.8± 4.1 years received 4±1.9 medications (range 1-12), of which 2.0±1.3 (range 0-6) contained lactose. Of 122 identified products, 51 (42%) contained 103.9±70.7 (22.4-320) mg of lactose per capsule or tablet. Potential daily lactose exposure per patient regimen was 563.4±573.2 (0-2071), median 340.2 mg. Two regimens contained more than 2 g and eight contained 1,501-2,000 mg. The majority (59%) of regimens contained 500 mg or less of lactose per day.

Conclusion: Although a substantial proportion of identified products contained lactose, daily ingested quantities were unlikely to cause symptoms in most lactose-intolerant patients. Research to determine the minimum quantity of lactose capable of causing symptoms in sensitive patients is required. Ready access to medication lactose content would facilitate identification of problematic regimens in "at-risk" patients (e.g., elderly, specific ethnic groups).

Key Words: Adverse drug reactions, Ambulatory care, Elderly, Excipients, Lactose, Lactose intolerance, Medications.

Abbreviations Used: p.r.n. = as needed; S.D. = standard deviation; NDC = National Drug Code.

Consult Pharm 1997;12: 259-65.

Lactose has long been used as a soluble excipient in the manufacture of orally administered pharmaceuticals. It is stable, inexpensive, and has a fast dissolution rate.¹ Although considered an inactive ingredient devoid of serious toxicity, lactose in widely varying amounts can induce symptoms in some lactase-deficient patients.^2,3

Lactase deficiency can be classified as a primary or a secondary event. Most primary lactase deficiency does not occur in infancy; rather, its onset is later in life, even though the deficiency is a genetically determined trait.⁴ Secondary deficiency occurs after intestinal mucosal injury as a result of infection, medications, gastrointestinal surgery, or toxins.⁵ Some drugs, including neomycin,⁶ kanamycin,⁶ colchicine,⁷ amino-salicylic acid,⁸ and chemotherapeutic agents⁹ have been reported to cause mucosal damage, resulting in sometimes irreversible lactose intolerance.

Levels of intestinal lactase vary widely among ethic groups, but low levels are common in almost all areas of the world with the exception of some areas of Europe and the Middle East. Lactase deficiency is most prevalent in Native Americans, Africans, and Southeast Asians, approaching 100%. In North American adults, lactase deficiency has been reported to occur in 62%-100% of Native Americans, 58%-100% of African Americans, 26%-53% of Hispanics, almost 100% of Asians, and 10%-75% of Caucasians.⁴

Absent or reduced lactase activity allows passage of undigested lactose and an abnormal fluid volume into the colon and, in some individuals, results in the clinical syndrome of lactose intolerance. Patients may present with abdominal distension, cramping, nausea, flatus, pain, and diarrhea. Symptom development depends on many factors, including the dose presented to the small bowel per unit of time, gastric emptying rate, intestinal transit time, and composition of the lactose carrier (i.e., lactose in water, whole milk, skim milk, solid).⁵

Diagnosis of lactose intolerance is based on a patient's clinical presentation and the results of diagnostic testing. Testing usually occurs after challenging subjects with a pharmacologic oral bolus of lactose 50 g after an eight-hour fast.^5,10 Such doses are generally effective in identifying lactase-deficient individuals. However, people differ in their subjective awareness of lactase deficiency and in the quantity of lactose that can be ingested without inducing perceived symptoms of intolerance.

Some investigators have suggested that lactose intolerance with lactose typically found in an eight-ounce glass of milk (12 g) is a relatively uncommon phenomenon,^10-12 despite the perception of severe intolerance by patients.¹¹ A recent randomized, double-blind crossover trial in 21 patients with documented lactase deficiency and self-reported severe intolerance used a challenge dose of milk (240 mL containing 12.1 g of lactose) versus the same quantity of lactose-hydrolyzed milk daily for one week. No significant difference in gastrointestinal symptom scores was detectable between groups.¹¹

A more recent randomized, crossover, double-blind study challenged 39 lactose maldigesters and 15 digesters to 0, 0.5, 1.5, and 7.0 g of lactose in lactose-hydrolyzed milk. These investigators also demonstrated that gastrointestinal symptoms appear to be induced by something other than the lactose content of the milk.¹² The authors of both studies concluded that many patients improperly attribute gastrointestinal symptoms to small quantities of lactose found in milk.^11,12

Some lactase-deficient patients, however, have reportedly developed symptoms of lactose intolerance from as little as 3 g of the sugar.^2,3 One study attempted to determine a symptom threshold in lactase-deficient subjects and demonstrated that 25% of the patient sample became symptomatic after ingesting 6 g. Ten percent of subjects developed symptoms after only three grams. The small study included 20 patients, median age 44 years (range 18-70), of whom 80% were of African-American descent.³ Unfortunately, similar data for the elderly and a wider variety of ethnic groups are not available.

Reported cases of lactose intolerance have also been attributed to the lactose filler used as an excipient in oral pharmaceuticals. Implicated drugs include flutamide,¹³ lithium carbonate,¹⁴ flurazepam hydrochloride,¹⁴ tranylcypromine sulfate,¹⁵ cromolyn sodium capsules,¹⁶ and acyclovir.¹⁷ Each of these reports involved patients with histories of lactose intolerance or documented lactase deficiency whose symptoms resolved after discontinuation of the lactose-containing product. Patient symptoms either improved or disappeared when the implicated lactose-containing product was continued in the presence of an oral lactase supplement or when the same agent, in a lactose-free formulation, was substituted. The patient on inhaled cromolyn was reported to have documented complete lactase deficiency.¹⁶

While manufacturers now voluntarily list inactive ingredients on product labeling,¹⁸ the specific quantity is not published. Approximately 35% of the community-based elderly receive four or more drugs daily.¹⁹ Whether the quantity of lactose excipient contained in patient regimens is sufficient to cause symptoms is not known. The hypothesis tested is that there may be a high prevalence of lactose in pharmaceuticals and that patient regimens may contain quantities previously reported to cause symptoms in lactose-intolerant individuals.

The objectives of this study were twofold: (1) to determine the prevalence of lactose as an excipient in the oral pharmaceuticals typically prescribed for ambulatory elderly patients in our setting, and (2) to quantify the potential daily lactose exposure (as pharmaceutical excipient) in the drug regimens of these patients.

Methods

All Medication Action Profiles^a received in an inner-city Veterans Affairs Medical Center outpatient pharmacy were obtained over a five-day sample period from January 31 through February 4, 1994. Study patients were selected from the general ambulatory clinic population to avoid focusing on a particular class of agents or disease. These Action Profiles were labeled with a temporary marker and then numbered sequentially. Patients were excluded if they were less than 60 years old or were not receiving oral medications at the time of the study ("out-of-scope" patients). Using a random numbers table, 100 "within-scope" patients were then selected for analysis.

Patient age, date of birth, gender, and marked profile number were recorded. The drug product name (brand and generic), strength, dosage form, and prescribed dose were recorded for each oral medication on every "within-scope" profile. The manufacturer name and product National Drug Codes of the dispensed medications were obtained from the outpatient pharmacy. Once the data were collected from the "within-scope" patient profiles, the profiles were unmarked to assure patient confidentiality.

Lactose content of the prescribed products was determined by telephoning the product's manufacturer. To compute the amount of lactose per patient regimen, we assumed a "worse case scenario." Daily lactose content of "as needed" (p.r.n.) medications was calculated based on the maximum quantity potentially ingested if taken according to the physician's directions. For products for which the manufacturer would only disclose a quantity range, we assigned the product's lactose content as the highest value in the stated range. When a lactose-containing product's quantity was not disclosed, we assigned its value as the maximum amount contained of all the drug products evaluated during the study. The total daily amount of lactose per patient medication regimen was then calculated.

Results

Patient selection and demographic characteristics are detailed in Table 1. A total of 533 outpatient Action Profiles were available for review during the study period. To obtain the 100 "within-scope" profiles, 153 profiles were randomly identified. Subsequently, 53 profiles were excluded as being "out-of-scope" for the following reasons: 47 were for patients under 60 years old, five patients were not receiving oral medications, and one patient was under 60 years old and receiving no oral medications. Based on the information presented in Table 1, the typical patient was a 70-year-old man receiving an average of four different medications.

Table 1. Patient Demographics and Lactose Exposure

Variable	Number or Amounta
No. patient pharmacy profiles	533
No. randomly selected profiles	153
No. "within-scope" profiles	100
No. Men	99
Mean age (years; S.D.; range)	68.8 ± 4.1 (60-87)
Total no. identified drug products	122
No. products containing lactose (% of total)	51 (42%)
No. patient regimens containing lactose	81 (81%)
Total no. drugs per patient regimen	4.0 ± 1.9 (1-12), 4.0
No. lactose-containing drugs per regimen	2.0 ± 1.3 (0-6), 2.0
Mean daily lactose exposure per regimen (S.D.; range; median)	563.4 ± 573.2 (0-2071), 340.2

a When appropriate, data are presented as Mean ± S.D. (Range),Median

In all, 41 pharmaceutical companies were contacted to determine the specific lactose content of 122 products. Most companies willingly disclosed this information. Seven manufacturers of 15 different drug products acknowledged that their products contained lactose but were unwilling to reveal the specific quantity, even when asked to identify a range of lactose content rather than a specific amount. The prevailing reason for not disclosing this information was the stated desire to maintain proprietary secrecy.

Of the 122 drug products in the patient regimens, 51 (42%) contained lactose. These products represented a diverse selection of therapeutic classes. Slightly more than one half (26/51) were cardiovascular agents, including anticoagulants, antihypertensives, antilipemics, digoxin, diuretics, and vasodilators. The remaining drugs were distributed widely among other therapeutic classes: central nervous system agents (nine products), hormones and synthetic substitutes (four products), and gastrointestinal drugs (three products). Of the 45 cardiovascular products identified in the study, 26 (58%) contained lactose. The distribution of lactose content in the dosage forms identified in the study are presented in Figure 1. The mean reported lactose content per tablet or capsule was 103.9 ± 70.7 mg (range 22.4-320). The median content was 77.0 mg. The majority of products contained 51-100 mg of lactose.

Figure 1. Lactose Content per Solid Oral Dosage Form

A mean of 2.0 ± 1.3 (range 0-6) lactose-containing drugs was found per patient regimen. Potential daily lactose exposure is presented in Figure 2. A wide range of exposure in the patient regimens was identified. The mean maximum amount of lactose potentially ingested on a daily basis was 563.4 ± 573.2 mg (range 0-2071) with a median of 340.2 mg. The majority of patient regimens contained 500 mg per day or less. Two patients had regimens with a potential daily exposure exceeding 2,000 mg. As the number of drugs in the patient regimens increased, the potential daily lactose exposure increased correspondingly.

Figure 2. Daily Lactose Content in Drug Regimens of Study Subjects

Discussion

Intestinal lactase activity declines with age. In addition, the number of medications in typical drug regimens typically increases with age. In this study, the prevalence of lactose as a pharmaceutical excipient was 42% in the patient regimens randomly selected. Over one half of the lactose-containing products were cardiovascular agents, and more than one half of the cardiovascular agents identified contained lactose. Patients treated for conditions in which multiple drug regimens are usual (e.g., elderly, cardiovascular disease) or less healthy patients on more medications would have higher daily lactose exposure.

As a number of lactose-containing products had unspecified lactose content, we chose to impute the maximum amount of lactose per dosage form found in the study for these products. This, in most likelihood, skewed the results toward an overestimation, given that most products may have contained substantially smaller amounts on the whole. Further, when ingested as an excipient in a medication regimen, lactose is generally presented in several doses over the course of a day as the patient takes the prescribed regimen. The lactose content in the study patients' daily drug regimens was far below that found in a serving of many dairy foods (Table 2), even with these possibly high estimates of lactose content.

Table 2. Lactose Content in Common Dairy Foods^a

Product	Serving Size	Lactose Content (g)
Milk	1 cup	9-13
Ice cream (vanilla)	1 cup	9
Cream, half and half	1 tbsp.	0.6
Yogurt, low-fat	1 cup	11-15
Cottage cheese (creamed)	1 cup	5-6
Cheese, Swiss or American	1 oz.	0.4-0.6

a Adapted from reference 2

The ability to tolerate lactose is not an "all or none" phenomenon; the severity of symptoms depends greatly on the quantity and form of lactose consumed as well as an individual's sensitivity. Symptoms of lactose intolerance are nonspecific and may be attributed to a number of other factors. In this study, when using a high estimate, we identified only a few patients with regimens containing lactose in a quantity that approaches the minimum amount previously reported to induce symptoms in a small study mostly of African-American patients.⁴ Case reports ^13-17 suggest that even smaller quantities may be capable of inducing symptoms in some patients. Overall, even in this elderly population receiving multiple medications, the quantity of lactose found in the majority of the patient regimens is unlikely to cause clinical intolerance in most lactose-intolerant patients.

Controlled studies to determine the minimum quantity of lactose capable of inducing symptoms in other patient groups are lacking. Additional study is required to identify patients at risk for lactose exposure in their medication regimens. Of particular interest would be evaluation of specific ethnic groups that may be exquisitely sensitive to lactose. It is likely that elderly nursing home residents taking a large number of medications would have higher lactose exposure and would therefore be at an increased risk.

Lactose has been extensively used in pharmaceutical preparations as an inert carrier of active ingredients. However, the debate on the clinical relevance of lactose as a pharmaceutical excipient in those who are lactose intolerant has long been divided, especially given the case reports of intolerance attributed to lactose fillers. A few of the manufacturers identified during this study admitted to receiving several telephone calls per month from both consumers and health professionals inquiring about the lactose content in their drug products. They reported that these calls were usually made on behalf of patients with pre-existing lactose intolerance. As manufacturers enter new markets, particularly in other countries with substantial populations of lactose-intolerant ethnic groups, results of additional research in this area could become particularly important.

Table 3. Lactose Content of Medications Encountereda

Lactose Content per Dosage Form (mg)	Product
< 100	baclofen 10 mg (Zenith)
	captopril 25, 50 mg (Squibb)
	colchicine 0.6 mg (Rugby)
	desipramine 50 mg (Goldline)
	digoxin 0.125 mg (Burroughs-Wellcome)
	doxazosin 2, 8 mg (Pfizer-Roerig)
	estrogens, conjugated 0.625 mg (Ayerst)
	furosemide 40 mg (Roxane)
	hydrochlorothiazide 25 mg (Zenith)
	hydrochlorothiazide 50 mg (Lederle)
	isosorbide oral 10 mg (Westward)
	isradipine 2.5 mg (Sandoz)
	levothyroxine 0.025, 0.15 mg (Boots)
	metoclopramide 10 mg (Rugby)
	metoprolol 50, 100 mg (Ciba-Geigy)
	nitroglycerin 0.4 mg (Parke-Davis)
	phenytoin extended 100 mg (Parke-Davis)
	prednisone 1 mg (Roxane)
	primidone 250 mg (Ayerst)
	prochlorperazine 10 mg (SmithKline Beecham)
100-149	bromocriptine 2.5 mg (Sandoz)
	digoxin 0.25 mg (Burroughs-Wellcome)
	lovastatin 20 mg (Merck Sharp & Dohme)
	oxybutynin 5 mg (Sidmak)
150-199	enalapril 5 mg (Merck & Co)
	metronidazole 250 mg (Lemmon)
200-249	indomethacin 25 mg (Mutual)
	warfarin 2, 2.5, 5 mg (DuPont)
250-299	loxapine 25 mg (Lederle)
300-320	diltiazem 60 mg (Lederle)
Lactose containing, but manufacturer would not disclose amount	allopurinol 100 mg (Rugby)
	allopurinol 300 mg (Warner-Chilcott)
	amitriptyline 25 mg (Geneva)
	aspirin, enteric coated 325 mg (Time-Cap)
	diphenhydramine 25 mg (Goldline)
	diphenoxylate 2.5 mg/atropine 0.025 mg (Geneva)
	imipramine 25 mg (Rugby)
	meclizine 25 mg (Rugby)
	nifedipine 30, 60, 90 mg SR (Miles)
	propranolol 40 mg (Warner-Chilcott)
	pseudoephedrine 60 mg (Geneva)
	triamterene 50 mg/hydrochlorothiazide 25 mg (Geneva)
	verapamil 80 mg (Purepac)

a Data obtained through telephone requests from manufacturers.

Conclusion

This study sought to determine the frequency of use of lactose as an excipient in pharmaceuticals and to quantify the potential exposure in elderly ambulatory patients. In our random sample of ambulatory elderly veterans, we determined that a large proportion (42%) of patient regimens contained lactose. However, the median daily potential exposure was under 500 mg, far below amounts demonstrated to induce symptoms in the vast majority of lactose-intolerant individuals. Only 10% of our patient regimens contained lactose in amounts approaching that previously reported in clinical trials to induce symptoms in a small proportion of patients.

These study results suggest that it is unlikely that lactose fillers will play an important clinical role in inducing gastrointestinal symptoms in this elderly ambulatory study population. However, the possibility still exists that patients, especially the elderly on complicated multidrug regimens, may approach a lactose load capable of causing symptoms in sensitive individuals. In the absence of studies that determine the minimum quantity of lactose capable of causing symptoms in specific ethnic populations, one cannot be totally confident that a lactose excipient cannot play a role in inducing symptoms in a specific lactose-intolerant individual.

Despite the negative results obtained in this evaluation, health care professionals should be aware of the possibility that an unusually sensitive lactose-intolerant individual could develop symptoms, particularly when the regimen contains a large number of lactose-containing medications. In this situation, the lactose content of the patient's regimen should be determined, and if substantial, a trial of a lactose-free formulation or lactase supplement may be warranted.

When determining lactose content of a regimen, pharmacists are cautioned to determine the lactose content for a specific product formulation. The lactose content in a dosage form may vary, not only between manufacturers, but also between product strengths. Ready access to lactose content of medications would facilitate identification of problematic regimens in particularly sensitive patients. Manufacturers are encouraged to make this information more readily accessible to health care providers.

a An Action Profile is a printout of a patient's active medication profile formatted to allow for renewal, cancellation, or refill of the prescriptions directly on the profile. New prescriptions can also be written directly on the document.

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