- Email: [email protected]
My first drug information question: Should my wife and baby be participants in an uncontrolled clinical trial?
letters
to a more promising pharmacy future. Maybe in some way we can get back to there. Michael J. Schuh, BS, PharmD, MBA Ambulatory Pharmacist Department of Pharmacy Mayo Clinic Jacksonville, FL [email protected] doi: 10.1331/JAPhA.2008.08051
My first drug information question: Should my wife and baby be participants in an uncontrolled clinical trial? I am a first-year student pharmacist with only a novice’s knowledge of pharmacotherapy and limited exposure to the principles of drug information. My first real drug information question was not a hypothetical exercise in the classroom. It involved my wife, my new baby boy, and the off-label prescribing of metoclopramide (Reglan—Wyeth). My wife was having difficulty breastfeeding our new baby, so she made an appointment with her physician. He prescribed metoclopramide and told her the drug would help, and she was sent on her way to have the prescription filled without any further explanation. I knew little about metoclopramide or what it was used to treat. In our first professional year drug information class, we had been admonished that if we were unfamiliar with a drug, the professional product labeling approved by the Food and Drug Administration (FDA) was a good place to start. In class, we also had discussions of the potential serious risks to patients when drugs are prescribed off label for uses that had not been approved by FDA. When my wife showed me her prescription, we were with a classmate who has a reputation as a “techie.” Being curious, we wanted to quickly know about metoclopramide. We had no reference resources or computer available, so we used my classmate’s smart phone to access the website DailyMed. This website is a cooperative program between FDA and the National Library of Medicine (NLM) that will eventually make avail444 • JAPhA • 4 8 : 4 • J u l /A u g 2 0 0 8
able, free of charge, professional product labels, or package inserts, for all drugs marketed in the United States.1 From metoclopramide’s professional label, we found that the drug is approved for the prevention of nausea and vomiting in patients with diabetic gastroparesis and for the prevention of heartburn in patients with gastroesophageal reflux disease. Lactation is not an FDA-approved use for the drug, but we did find galactorrhea listed as an adverse effect.2 My wife laughed and asked whether, because metoclopramide is not approved for lactation, my classmate and I were going to try and talk her out of filling the prescription. We then read her a few of the adverse effects from the drug’s professional label, such as depression, suicidal thoughts, and involuntary movements of the limbs and face, which can be irreversible. Metoclopramide is also excreted in breast milk, potentially exposing our new baby to the drug.2 After discussing the risks of the drug and its unknown ability to induce lactation, she had no desire to have her metoclopramide prescription filled. In fact, she was shocked that her physician would prescribe her a drug for an off-label use and not mention the benefits and risks. The next day, we saw our drug information professor and told him our metoclopramide story. He said that accessing metoclopramide’s package insert was a good first step. In our conversation, we wondered what we would have found if the only source of information we used was Google. This professor is critical of those who use Google as their firstchoice drug information source. But we tried it for openers, searching on metoclopramide and lactation. The first hit was a link to an article titled “Use of Reglan to increase milk supply” at www. breastfeeding.org. This site is operated by the San Diego County Breastfeeding Coalition. The article indicated that metoclopramide has been shown to successfully induce lactation and is the preferred agent because of its safety and relative lack of adverse effects.3 We wondered how the off-label prew w w.j a p h a . o r g
scribing of metoclopramide for lactation became a practice. Our professor indicated he was not sure but suggested that we do a Medline search using metoclopramide and lactation as search terms, looking for the first citation describing the use of the drug to promote lactation. We found a letter to the editor published in the British Medical Journal in 1975. Five women were reported to have been successfully treated with metoclopramide for breast-feeding.4 This was an uncontrolled clinical observation and hardly the level of evidence that should be used to prescribe a drug with known serious risks to healthy new mothers. A number of the citations from our MedLine search lacked randomization, blinding, or a control group.4–8 When the search was limited to randomized controlled trials, we found just two such blinded trials. The first studied women who delivered by cesarean section, and the second looked at women who delivered preterm infants. Neither study could differentiate metoclopramide from placebo.9,10 We also searched the LactMed database, which was a resource recommended in our drug information class, for metoclopramide. LactMed is a peerreviewed, fully referenced database on drugs and breast-feeding sponsored by NLM that is available free of charge online.11 The LactMed information concluded that when new mothers were taught breast-feeding techniques, the addition of metoclopramide gave no additional benefit.12 My wife successfully used these techniques with our baby. Because of time constraints, we did not conduct an exhaustive systematic review of the topic, as this was a clinical question. I felt comfortable that we had recommended that my wife not have the metoclopramide prescription filled. She and the baby did not become unwitting participants in an uncontrolled experiment in which she was not offered the opportunity to provide informed consent. This episode taught us that applying a few basic drug information principles
Journal of the American Pharmacists Association
letters
and a search of the literature can make a difference, even in the hands of students early in their studies. We were able to access drug information using free databases on available and reliable government websites such as DailyMed, LactMed, and Medline. If Google had been used as our sole source of information, my wife and new baby would have been exposed to a medication with serious adverse effects with no proven clinical benefit. Also, nonpharmacologic interventions are often overlooked and can provide us with counseling opportunities on these simple but effective strategies. This situation also opened our eyes to the potential harm that off-label prescribing can present to the uninformed patient when prescribing practice is not centered on evidence-based medicine. The bottom line is that mother and baby are doing fine.
Larry Sasich, PharmD, MPH, FASHP Assistant Professor of Pharmacy Practice School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA
9. Hansen WF, McAndrew S, Harris K, Zimmerman MB. Metoclopramide effect on breastfeeding the preterm infant: a randomized trial. Obstet Gynecol. 2005;105:383–9.
doi: 10.1331/JAPhA.2008.08053
10. Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol. 1980;9:217–9.
Stephen Brown Student Pharmacist School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA [email protected]
6. Habbick BF, Gerrard JW. Failure to thrive in the contented breast-fed baby. Can Med Assoc J. 1984;131:765–8.
Phillip Olsen Student Pharmacist School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA
446 • JAPhA • 4 8 : 4 • J u l /A u g 2 0 0 8
References
1. National Library of Medicine. DailyMed. Accessed at http://dailymed.nlm.nih. gov/dailymed/about.cfm, April 17, 2008. 2. Actavis Elizabeth LLC. Metoclopramide (Reglan) professional product label. Accessed at http://dailymed.nlm.nih. gov/dailymed/drugInfo.cfm?id= 6271, April 17, 2008. 3. San Diego Breastfeeding Coalition. Use of Reglan (metoclopramide) to increase milk supply. Accessed at www.breastfeeding.org/articles/reglan2.html, April 17, 2008. 4. Sousa PL. Letter: metoclopramide and breast-feeding. BMJ. 1975;1:512. 5. Gabay MP. Galactogogues: medications that induce lactation. J Hum Lact. 2002;18:274–9.
7. Kauppila A, Kivinen S, Ylikorkala O. A dose response relation between improved lactation and metoclopramide. Lancet. 1981;1:1175–7. 8. de Gezelle H, Ooghe W, Thiery M, Dhont M. Metoclopramide and breast milk. Eur J Obstet Gynecol Reprod Biol. 1983;15:31–6.
w w w.j a p h a . o r g
11. U.S. National Library of Medicine. Drugs and lactation database (LactMed). Accessed at http://toxnet.nlm.nih.gov/cgibin/sis/htmlgen?LACT, April 17, 2008. 12. U.S. National Library of Medicine. Metoclopramide. Accessed at http://toxnet. nlm.nih.gov, April 17, 2008.
Correction OTC Product: Tums QuikPak, May/ June 2008, page e68. The final sentence of the Discussion section should read as follows: “[Calcium carbonate] is considered a nonsystemic antacid because the calcium salts formed are not absorbed completely.” (The word “completely” was not in the original.) No oral calcium supplement is ever completely absorbed; several references quote calcium carbonate as being 15% to 35% absorbed, depending on several factors. doi: 10.1331/JAPhA.2008.08057
Journal of the American Pharmacists Association
to a more promising pharmacy future. Maybe in some way we can get back to there. Michael J. Schuh, BS, PharmD, MBA Ambulatory Pharmacist Department of Pharmacy Mayo Clinic Jacksonville, FL [email protected] doi: 10.1331/JAPhA.2008.08051
My first drug information question: Should my wife and baby be participants in an uncontrolled clinical trial? I am a first-year student pharmacist with only a novice’s knowledge of pharmacotherapy and limited exposure to the principles of drug information. My first real drug information question was not a hypothetical exercise in the classroom. It involved my wife, my new baby boy, and the off-label prescribing of metoclopramide (Reglan—Wyeth). My wife was having difficulty breastfeeding our new baby, so she made an appointment with her physician. He prescribed metoclopramide and told her the drug would help, and she was sent on her way to have the prescription filled without any further explanation. I knew little about metoclopramide or what it was used to treat. In our first professional year drug information class, we had been admonished that if we were unfamiliar with a drug, the professional product labeling approved by the Food and Drug Administration (FDA) was a good place to start. In class, we also had discussions of the potential serious risks to patients when drugs are prescribed off label for uses that had not been approved by FDA. When my wife showed me her prescription, we were with a classmate who has a reputation as a “techie.” Being curious, we wanted to quickly know about metoclopramide. We had no reference resources or computer available, so we used my classmate’s smart phone to access the website DailyMed. This website is a cooperative program between FDA and the National Library of Medicine (NLM) that will eventually make avail444 • JAPhA • 4 8 : 4 • J u l /A u g 2 0 0 8
able, free of charge, professional product labels, or package inserts, for all drugs marketed in the United States.1 From metoclopramide’s professional label, we found that the drug is approved for the prevention of nausea and vomiting in patients with diabetic gastroparesis and for the prevention of heartburn in patients with gastroesophageal reflux disease. Lactation is not an FDA-approved use for the drug, but we did find galactorrhea listed as an adverse effect.2 My wife laughed and asked whether, because metoclopramide is not approved for lactation, my classmate and I were going to try and talk her out of filling the prescription. We then read her a few of the adverse effects from the drug’s professional label, such as depression, suicidal thoughts, and involuntary movements of the limbs and face, which can be irreversible. Metoclopramide is also excreted in breast milk, potentially exposing our new baby to the drug.2 After discussing the risks of the drug and its unknown ability to induce lactation, she had no desire to have her metoclopramide prescription filled. In fact, she was shocked that her physician would prescribe her a drug for an off-label use and not mention the benefits and risks. The next day, we saw our drug information professor and told him our metoclopramide story. He said that accessing metoclopramide’s package insert was a good first step. In our conversation, we wondered what we would have found if the only source of information we used was Google. This professor is critical of those who use Google as their firstchoice drug information source. But we tried it for openers, searching on metoclopramide and lactation. The first hit was a link to an article titled “Use of Reglan to increase milk supply” at www. breastfeeding.org. This site is operated by the San Diego County Breastfeeding Coalition. The article indicated that metoclopramide has been shown to successfully induce lactation and is the preferred agent because of its safety and relative lack of adverse effects.3 We wondered how the off-label prew w w.j a p h a . o r g
scribing of metoclopramide for lactation became a practice. Our professor indicated he was not sure but suggested that we do a Medline search using metoclopramide and lactation as search terms, looking for the first citation describing the use of the drug to promote lactation. We found a letter to the editor published in the British Medical Journal in 1975. Five women were reported to have been successfully treated with metoclopramide for breast-feeding.4 This was an uncontrolled clinical observation and hardly the level of evidence that should be used to prescribe a drug with known serious risks to healthy new mothers. A number of the citations from our MedLine search lacked randomization, blinding, or a control group.4–8 When the search was limited to randomized controlled trials, we found just two such blinded trials. The first studied women who delivered by cesarean section, and the second looked at women who delivered preterm infants. Neither study could differentiate metoclopramide from placebo.9,10 We also searched the LactMed database, which was a resource recommended in our drug information class, for metoclopramide. LactMed is a peerreviewed, fully referenced database on drugs and breast-feeding sponsored by NLM that is available free of charge online.11 The LactMed information concluded that when new mothers were taught breast-feeding techniques, the addition of metoclopramide gave no additional benefit.12 My wife successfully used these techniques with our baby. Because of time constraints, we did not conduct an exhaustive systematic review of the topic, as this was a clinical question. I felt comfortable that we had recommended that my wife not have the metoclopramide prescription filled. She and the baby did not become unwitting participants in an uncontrolled experiment in which she was not offered the opportunity to provide informed consent. This episode taught us that applying a few basic drug information principles
Journal of the American Pharmacists Association
letters
and a search of the literature can make a difference, even in the hands of students early in their studies. We were able to access drug information using free databases on available and reliable government websites such as DailyMed, LactMed, and Medline. If Google had been used as our sole source of information, my wife and new baby would have been exposed to a medication with serious adverse effects with no proven clinical benefit. Also, nonpharmacologic interventions are often overlooked and can provide us with counseling opportunities on these simple but effective strategies. This situation also opened our eyes to the potential harm that off-label prescribing can present to the uninformed patient when prescribing practice is not centered on evidence-based medicine. The bottom line is that mother and baby are doing fine.
Larry Sasich, PharmD, MPH, FASHP Assistant Professor of Pharmacy Practice School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA
9. Hansen WF, McAndrew S, Harris K, Zimmerman MB. Metoclopramide effect on breastfeeding the preterm infant: a randomized trial. Obstet Gynecol. 2005;105:383–9.
doi: 10.1331/JAPhA.2008.08053
10. Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol. 1980;9:217–9.
Stephen Brown Student Pharmacist School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA [email protected]
6. Habbick BF, Gerrard JW. Failure to thrive in the contented breast-fed baby. Can Med Assoc J. 1984;131:765–8.
Phillip Olsen Student Pharmacist School of Pharmacy Lake Erie College of Osteopathic Medicine Erie, PA
446 • JAPhA • 4 8 : 4 • J u l /A u g 2 0 0 8
References
1. National Library of Medicine. DailyMed. Accessed at http://dailymed.nlm.nih. gov/dailymed/about.cfm, April 17, 2008. 2. Actavis Elizabeth LLC. Metoclopramide (Reglan) professional product label. Accessed at http://dailymed.nlm.nih. gov/dailymed/drugInfo.cfm?id= 6271, April 17, 2008. 3. San Diego Breastfeeding Coalition. Use of Reglan (metoclopramide) to increase milk supply. Accessed at www.breastfeeding.org/articles/reglan2.html, April 17, 2008. 4. Sousa PL. Letter: metoclopramide and breast-feeding. BMJ. 1975;1:512. 5. Gabay MP. Galactogogues: medications that induce lactation. J Hum Lact. 2002;18:274–9.
7. Kauppila A, Kivinen S, Ylikorkala O. A dose response relation between improved lactation and metoclopramide. Lancet. 1981;1:1175–7. 8. de Gezelle H, Ooghe W, Thiery M, Dhont M. Metoclopramide and breast milk. Eur J Obstet Gynecol Reprod Biol. 1983;15:31–6.
w w w.j a p h a . o r g
11. U.S. National Library of Medicine. Drugs and lactation database (LactMed). Accessed at http://toxnet.nlm.nih.gov/cgibin/sis/htmlgen?LACT, April 17, 2008. 12. U.S. National Library of Medicine. Metoclopramide. Accessed at http://toxnet. nlm.nih.gov, April 17, 2008.
Correction OTC Product: Tums QuikPak, May/ June 2008, page e68. The final sentence of the Discussion section should read as follows: “[Calcium carbonate] is considered a nonsystemic antacid because the calcium salts formed are not absorbed completely.” (The word “completely” was not in the original.) No oral calcium supplement is ever completely absorbed; several references quote calcium carbonate as being 15% to 35% absorbed, depending on several factors. doi: 10.1331/JAPhA.2008.08057
Journal of the American Pharmacists Association