Pyridoxine/doxylamine

Last updated
Pyridoxine/doxylamine
Combination of
Pyridoxine Vitamin
Doxylamine Antihistamine
Clinical data
Trade names Diclegis, Bendectin, Debendox, Lenotan, Merbental, Diclectin, others
Pregnancy
category
  • Compatible
Routes of
administration 		By mouth
Legal status
Legal status
  • CA:Approved
  • US:Approved
  • Prescription only; approved drug in Israel
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
   (verify)

Pyridoxine/doxylamine, sold under the brand name Diclectin among others, is a combination of pyridoxine hydrochloride (vitamin B6) and doxylamine succinate. It is generally used for nausea and vomiting of pregnancy (morning sickness); even though its efficacy has not been proven and subsequent research has led to the removal of recommendations in medical journals. [1] [2]

Contents

Medical uses

The combination of pyridoxine, commonly referred to as vitamin B6 and doxylamine may be an effective for the management of nausea and vomiting of pregnancy, [3] but it is only recommended for use in a small number of cases after lifestyle, diet and vitamin B6. A 2018 review found the benefit was small. [1]

Doxylamine and pyridoxine are pregnancy compatible drugs, [4] consistent with FDA's safety assessment of the combination product. They have been categorized by the FDA as a category A drug (no evidence of risk to the fetus). This letter classification system for risk in pregnancy is no longer being utilized and is currently being phased out by the FDA. [5]

Medical organizations’ position

The American Congress of Obstetricians and Gynecologists (ACOG) states "Safe and effective treatments are available for more severe cases, and mild cases of nausea and vomiting of pregnancy may be resolved with lifestyle and dietary changes." [6] The American Family Medicine recommends, "Initial treatment is conservative and includes dietary changes, emotional support, and vitamin B6 supplementation." [7] This treatment has a Grade A, "consistent, good-quality patient-oriented evidence " [7] while the addition of prescribing doxylamine has a Grade C, "consensus, disease-oriented evidence, usual practice, expert opinion, or case series." [7]

Canadian Family Physician issued a correction stating previous articles which stated Diclectin should be used as a first line therapy were incorrect, based upon undisclosed conflicts of interest with the manufacturer, and not peer-reviewed studies:

"Recommendations in 2 articles published in Canadian Family Physician, “Nausea and vomiting of pregnancy. Evidence-based treatment algorithm” and “Treatment of nausea and vomiting in pregnancy. An updated algorithm,” have subsequently come under critical scrutiny. These articles were not subjected to standard peer review, and Canadian Family Physician acknowledges that upon closer inspection these articles did not provide satisfactory evidence that would have justified the recommendation of doxylamine-pyridoxine as a sole first-line treatment for nausea and vomiting in pregnancy (NVP). More recent Canadian NVP guidelines have been published; however, a subsequent re-analysis questions the conclusions of 1 of the studies cited in these guidelines to justify doxylamine-pyridoxine as a recommended first-line treatment for NVP. Additionally, for the articles in Canadian Family Physician there was an undisclosed conflict of interest with Duchesnay, the manufacturer of Diclectin, the combination of doxylamine-pyridoxine. Canadian Family Physician encourages readers to interpret previously published NVP recommendations with caution. Readers are also referred to the commentary “Motherisk and Canadian Family Physician” in the January 2017 issue of Canadian Family Physician." [8] [Ed: bolding to help summarize information, note please follow link to article to see the footnotes from this article]

Adverse effects

Pyridoxine, vitamin B6, is a water-soluble vitamin and is generally recognized as having no adverse effects. [9] [10] After diet changes, it alone is recommended as the secondary treatment plan.

The most commonly reported adverse reaction of doxylamine is drowsiness. [11] Other adverse drug reactions associated with doxylamine succinate may include: vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention or insomnia. [10]

It is not recommended to take doxylamine with other medications of the same class, medications that act on the central nervous system (CNS) or with alcohol as this may increase the risk of adverse effects. [10] [11] To minimize the risk of particular adverse effects, doxylamine should not be used when taking any medication classified as a monoamine oxidase inhibitor (MAOI), and should be used with caution, if at all, when certain medical conditions are present. [10] [11]

Because doxylamine is small enough on a molecular weight basis to pass into breastmilk, women should not breastfeed while using products with doxylamine as this may lead to adverse effects in the breastfed infant. [10]

Safety in pregnancy

Due to the extensive scientific evidence demonstrating that there is no difference in the risk for birth defects or other adverse pregnancy outcomes between infants whose mothers take pyridoxine/doxylamine during pregnancy and those infants whose mothers do not take this drug combination, the two ingredients of the drug are considered pregnancy compatible [4] (or category A drugs with the previous pregnancy risk factor classification system).

Since the mid-1950s, over 33 million women have used the combination drug of pyridoxine/doxylamine in pregnancy, and scientific analysis on more than 200,000 exposed pregnancies has been conducted to determine if the combination of pyridoxine and doxylamine is harmful to the unborn baby. [12] [13] No epidemiological studies have found any teratogenic effect. [13]

Two separate meta-analyses have been conducted that have assessed pregnancy outcomes following the use of a combination of pyridoxine and doxylamine with or without dicyclomine during the first trimester of pregnancy. [14] [15] The initial meta-analysis, published in 1988, combined data from 12 cohort and 5 case-control studies, [14] and the subsequent meta-analysis, published in 1994, combined data from 16 cohort studies and 11 case control studies. [15] These studies included over 200,000 Bendectin-exposed pregnancies and did not observe an increased risk for major malformations. [14] [15] Separate analyses were conducted for specific defects including cardiac defects, limb reduction defects, oral clefts, and genital tract malformations; no increased risks for these defects were found. [15]

In 1989, a report on the safety of the drug combination of pyridoxine/doxylamine for use in the management of NVP was prepared by a panel of Canadian and American experts for the Special Advisory Committee on Reproductive Physiology to the Health Protection Branch of Health Canada (currently called the Health Products and Food Branch). [16] These scientific experts concluded that “numerous studies in animals and in humans that have been reported in the scientific and medical literature demonstrate that Bendectin is not a teratogen. The safety of Bendectin/Diclectin in the management of nausea and vomiting of pregnancy has been established by its use in many thousands of pregnant women”. [16]

A study was conducted to determine whether the combination drug of pyridoxine and doxylamine had an effect on the neurodevelopment of children exposed in utero. Results from this study observed no difference in intelligence quotient scores between children who were exposed to pyridoxine/doxylamine in utero and children who were not exposed. [17]

History

The combination of doxylamine and vitamin B6 was first introduced to the US market as Bendectin in 1956. At that time, Bendectin was a 3 ingredients prescription medication. The third one, dicyclomine, a Pregnancy Category B anticholinergic/antispasmodic, was omitted from the formulation starting in 1976 due to its lack of efficacy. [18] : 317  Bendectin (doxylamine/vitamin B6) was voluntarily removed from the market in 1983 by its manufacturer, Merrell Dow Pharmaceuticals, following numerous lawsuits alleging that it caused birth defects, although an FDA panel concluded that no association between Bendectin and birth defects had been demonstrated. [19] In litigation, Bendectin was implicated as the cause of various fetal malformations and problems including limb and other musculoskeletal deformities, facial and brain damage, defects of the respiratory, gastrointestinal, cardiovascular and genital-urinary systems, blood disorders and cancer. [19] The most famous case involving the drug is Daubert v. Merrell Dow Pharmaceuticals (1993). These suits were led by celebrity plaintiff attorney Melvin Belli . [20] The star witness for the case against Bendectin, William McBride, was later found to have falsified research on teratogenic effects of the drug, and was struck off the medical register in Australia. [21] [22]

An extensive review of the evidence submitted in legal proceedings regarding Bendectin has been summarized and found no evidence that the drug in clinical use was linked to birth defects. [23]

The FDA, in 1999, published a statement in the Federal Register that summarized their opinion regarding the safety of pyridoxine/doxylamine during pregnancy: “The FDA has determined that the drug product Bendectin, a tablet composed of pyridoxine hydrochloride 10 mg, and doxylamine succinate 10 mg, for the prevention of nausea of pregnancy was not withdrawn from the market for reasons of safety or effectiveness”.

On Monday April 8, 2013, the FDA approved the return of the doxylamine-pyridoxine combination under the new trademark name of Diclegis. The medication is manufactured by Duchesnay Inc, a company later shown to not disclose conflict of interests with authors, leading to Canadian Family Physician to correct several articles because of their behavior and the lack of research that shows that there was medically significant results. [8]

In July 2015, the drug company came under considerable scrutiny for promoting its drug through the American celebrity Kim Kardashian through the social media platforms Facebook and Instagram. [24] [25] [26] [27] [28]

In October 2015, Toronto, Canada physicians Drs. Navindra Persaud, Jessica Chin, and Mark Walker wrote a public letter to the Journal of Obstetrics and Gynaecology of Canada and raised concerns over the risks of Diclectin and recommended reconsidering it as the "first-line pharmacological treatment" against the nausea and vomiting of pregnancy. [29] Dr. Persaud shared with news agencies that his only source of research data for this drug came from Health Canada and claimed he was only able to access the document by signing a confidentiality agreement. [30] [31] [32]

In January 2019, Canadian Family Physician issued a correction stating "Recommendations in 2 articles published in Canadian Family Physician, “Nausea and vomiting of pregnancy. Evidence-based treatment algorithm” and “Treatment of nausea and vomiting in pregnancy. An updated algorithm,” have subsequently come under critical scrutiny. These articles were not subjected to standard peer review, and Canadian Family Physician acknowledges that upon closer inspection these articles did not provide satisfactory evidence that would have justified the recommendation of doxylamine-pyridoxine as a sole first-line treatment for nausea and vomiting in pregnancy (NVP). More recent Canadian NVP guidelines have been published; however, a subsequent re-analysis questions the conclusions of 1 of the studies cited in these guidelines to justify doxylamine-pyridoxine as a recommended first-line treatment for NVP. Additionally, for the articles in Canadian Family Physician there was an undisclosed conflict of interest with Duchesnay, the manufacturer of Diclectin, the combination of doxylamine-pyridoxine. Canadian Family Physician encourages readers to interpret previously published NVP recommendations with caution. Readers are also referred to the commentary “Motherisk and Canadian Family Physician” in the January 2017 issue of Canadian Family Physician." [8] [Ed: bolding to help summarize information, note please follow link to article to see the footnotes from this article]

Society and culture

From a legal perspective, the case through Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993) set a new standard for admitting expert testimony in federal courts in lieu of the Frye standard. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Thalidomide</span> Immunomodulatory drug known for its ability to cause birth defects

Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral medication used to treat a number of cancers, graft-versus-host disease, and many skin disorders. While thalidomide has been used in a number of HIV-associated conditions, such use is associated with increased levels of the virus.

An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

<span class="mw-page-title-main">Isotretinoin</span> Medication primarily used to treat severe acne

Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers, and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.

Morning sickness, also called nausea and vomiting of pregnancy (NVP), is a symptom of pregnancy that involves nausea or vomiting. Despite the name, nausea or vomiting can occur at any time during the day. Typically the symptoms occur between the 4th and 16th week of pregnancy. About 10% of women still have symptoms after the 20th week of pregnancy. A severe form of the condition is known as hyperemesis gravidarum and results in weight loss.

<span class="mw-page-title-main">Metoclopramide</span> Treatment for nausea & vomiting, emptying of stomach, GERD and used in migraines

Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the postanesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

<span class="mw-page-title-main">Dicycloverine</span> Antispasmodic agent

Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscle. While it has been used in baby colic and enterocolitis, evidence does not support these uses.

<span class="mw-page-title-main">Ondansetron</span> Medication to prevent nausea and vomiting

Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It is also effective for treating gastroenteritis. It can be given by mouth or by injection into a muscle or into a vein.

<span class="mw-page-title-main">Pyridoxine</span> Chemical compound

Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disorders, side effects or complications of isoniazid use, and certain types of mushroom poisoning. It is used by mouth or by injection.

William Griffith McBride CBE AO was an Australian obstetrician. He published a letter on the teratogenicity of thalidomide following the findings of a midwife named Pat Sparrow, which resulted in the reduction of the number of drugs prescribed during pregnancy. Later in his life, McBride was found guilty of separate counts of medical malpractice and scientific fraud for falsifying data in a paper that claimed that the drug Debendox was also responsible for birth defects.

Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), is a United States Supreme Court case determining the standard for admitting expert testimony in federal courts. In Daubert, the Court held that the enactment of the Federal Rules of Evidence implicitly overturned the Frye standard; the standard that the Court articulated is referred to as the Daubert standard.

<span class="mw-page-title-main">Doxylamine</span> First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)

Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. In combination with pyridoxine (vitamin B6), it is also used to treat morning sickness in pregnant women. Doxylamine is available over-the-counter, and is used in nighttime cold medicines, such as NyQuil, as well as in pain medications containing acetaminophen and codeine, to help with sleep. The medication is taken by mouth.

Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered more severe than morning sickness. Symptoms often get better after the 20th week of pregnancy but may last the entire pregnancy duration.

<span class="mw-page-title-main">Vilazodone</span> Medication used to treat major depressive disorder

Vilazodone, sold under the brand name Viibryd among others, is a medication used to treat major depressive disorder. It is taken by mouth.

<span class="mw-page-title-main">Nausea</span> Medical symptom or condition

Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.

Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Non-essential drugs and medications should be avoided while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may be dangerous for the unborn baby and may lead to severe health problems and/or birth defects. Even small amounts of alcohol, tobacco, and marijuana have not been proven to be safe when taken while pregnant. In some cases, for example, if the mother has epilepsy or diabetes, the risk of stopping a medication may be worse than risks associated with taking the medication while pregnant. The mother's healthcare professional will help make these decisions about the safest way to protect the health of both the mother and unborn child. In addition to medications and substances, some dietary supplements are important for a healthy pregnancy, however, others may cause harm to the unborn child.

<span class="mw-page-title-main">Meclizine</span> Chemical compound

Meclizine, sold under the brand name Bonine, among others, is an antihistamine used to treat motion sickness and dizziness (vertigo). It is taken by mouth. Effects generally begin in an hour and last for up to a day.

<span class="mw-page-title-main">Drospirenone/ethinylestradiol/levomefolic acid</span> Pharmaceutical combination

Drospirenone/ethinylestradiol/levomefolic acid (EE/DRSP/LMF), sold under the brand names Beyaz among others, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestogen, antimineralocorticoid, and antiandrogen, and levomefolic acid (LMF), a form of vitamin B9, which is used as a birth control pill to prevent pregnancy in women. The formulation contains folate as the calcium salt of levomefolic acid to lower the risk of complications such as fetal neural tube defects should the medication fail as a form of birth control. EE/DRSP/LMF was approved for use by the U.S. Food and Drug Administration (FDA) on 24 September 2010.

Signs and symptoms of pregnancy are common, benign conditions that result from the changes to the body that occur during pregnancy. Signs and symptoms of pregnancy typically change as pregnancy progresses, although several symptoms may be present throughout. Depending on severity, common symptoms in pregnancy can develop into complications. Pregnancy symptoms may be categorized based on trimester as well as region of the body affected.

Prenatal dental care is the care of the oral cavity during fetal development. The woman’s body is subject to hormonal changes leading to several physical changes in the oral cavity during pregnancy. Some of these changes may cause tooth decay, erosion and periodontal health changes.

References

  1. 1 2 Persaud N, Meaney C, El-Emam K, Moineddin R, Thorpe K (17 January 2018). "Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis". PLOS ONE. 13 (1): e0189978. Bibcode:2018PLoSO..1389978P. doi: 10.1371/journal.pone.0189978 . PMC   5771578 . PMID   29342163.
  2. ↑ Morning sickness drug Diclectin doesn't work, confidential industry documents reviewed by doctor show — Article published in "CBC news" on 17 January 2018
  3. ↑ Madjunkova S, Maltepe C, Koren G (June 2014). "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy". Paediatric Drugs. 16 (3): 199–211. doi:10.1007/s40272-014-0065-5. PMC   4030125 . PMID   24574047.
  4. 1 2 Briggs GG, Freeman RK. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition. 2015. Published by: Wolters Kluwer Health.
  5. ↑ "Pregnancy and Lactation Labeling (Drugs) Final Rule". US Food and Drug Administration. 2 March 2020.
  6. ↑ American College of Obstetricians and Gynecologists (ACOG). (April 2004). "Nausea and vomiting of pregnancy". ACOG Practice Bulletin. Washington (DC): American College of Obstetricians and Gynecologists (ACOG) (52).
  7. 1 2 3 Herrell, Howard Ernest (2014-06-15). "Nausea and Vomiting of Pregnancy". American Family Physician. 89 (12): 965–970. PMID   25162163.
  8. 1 2 3 "Recommendations in 2 articles published in Canadian Family Physician, "Nausea and vomiting of pregnancy. Evidence-based treatment algorithm"1 and "Treatment of nausea and vomiting in pregnancy. An updated algorithm,"2 have subsequently come under critical scrutiny". Canadian Family Physician. 65 (1): 8. January 2019. PMC   6347327 . PMID   30674506.
  9. ↑ Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine. (1998). "Vitamin B6". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press.{{cite book}}: CS1 maint: multiple names: authors list (link)
  10. 1 2 3 4 5 Duchesnay Inc. (8 March 2016). Diclectin Product Monograph (PDF)– via Health Canada’s Drug Product Database.
  11. 1 2 3 American Society of Health-System Pharmacists (AHFS) Drug Information 2014, Antihistamine Drugs. pgs 1-8.
  12. ↑ Koren G, Clark S, Hankins GD, Caritis SN, Miodovnik M, Umans JG, Mattison DR (December 2010). "Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial". American Journal of Obstetrics and Gynecology. 203 (6): 571.e1–7. doi:10.1016/j.ajog.2010.07.030. PMID   20843504.
  13. 1 2 Kutcher JS, Engle A, Firth J, Lamm SH (February 2003). "Bendectin and birth defects. II: Ecological analyses". Birth Defects Research. Part A, Clinical and Molecular Teratology. 67 (2): 88–97. doi:10.1002/bdra.10034. hdl: 2027.42/35295 . PMID   12769504.
  14. 1 2 3 Einarson TR, Leeder JS, Koren G (October 1988). "A method for meta-analysis of epidemiological studies". Drug Intelligence & Clinical Pharmacy. 22 (10): 813–24. doi:10.1177/106002808802201021. PMID   3229352. S2CID   33156399.
  15. 1 2 3 4 McKeigue PM, Lamm SH, Linn S, Kutcher JS (July 1994). "Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies". Teratology. 50 (1): 27–37. doi:10.1002/tera.1420500105. PMID   7974252.
  16. 1 2 Ornstein M, Einarson A, Koren G (1995). "Bendectin/diclectin for morning sickness: a Canadian follow-up of an American tragedy". Reproductive Toxicology. 9 (1): 1–6. doi:10.1016/0890-6238(94)00050-7. PMID   8520127.
  17. ↑ Nulman I, Rovet J, Barrera M, Knittel-Keren D, Feldman BM, Koren G (July 2009). "Long-term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and diclectin". The Journal of Pediatrics. 155 (1): 45–50, 50.e1-2. doi:10.1016/j.jpeds.2009.02.005. PMID   19394042.
  18. ↑ Sanders J (January 1992). "The Bendectin Litigation: A Case Study in the Life Cycle of Mass Torts". Hastings Law Journal. 43 (2): 301–418.
  19. 1 2 Brody JE (1983-06-19). "Shadow of Doubt Wipes Out Bendectin". New York Times.
  20. ↑ Korcok M (November 1980). "The Bendectin debate". Canadian Medical Association Journal. 123 (9): 922–8. PMC   1704894 . PMID   7437993.
  21. ↑ Thalidomide hero found guilty of scientific fraud — Article published in "New Scientist" on 27 February 1991
  22. ↑ Thalidomide doctor guilty of medical fraud — Article published in "The Independent" on 20 February 1993
  23. ↑ Brent RL (1995). "Bendectin: Review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen" (PDF). Reproductive Toxicology. 9 (4): 337–349. doi:10.1016/0890-6238(95)00020-B. PMID   7496090. Archived from the original (PDF) on 2011-07-16. Retrieved 2010-07-30.
  24. ↑ Kroll D (July 31, 2015). "The Kim Kardashian-Endorsed Morning Sickness Drug Is The Real Deal". Forbes. Retrieved 15 October 2015.
  25. ↑ "Kim Kardashian drug endorsement may break Canadian law: experts". Yahoo news. 7 Aug 2015. Retrieved 15 October 2015.
  26. ↑ Rinkunas S (19 July 2015). "How Safe Is the Morning-Sickness Drug Diclegis?". New York Magazine. Retrieved 15 October 2015.
  27. ↑ Blackwell T (11 August 2015). "FDA lashes out at drug company for promoting Canadian morning-sickness pill on Kardashian Instagram feed". National Post. Retrieved 15 October 2015.
  28. ↑ "Kim Kardashian's social media posts for morning-sickness violate drug promotion rules: FDA". Canadian Broadcasting Corporation. The Associated Press. 11 August 2015. Retrieved 15 October 2015.
  29. ↑ Persaud N, Chin J, Walker M (April 2014). "Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy?". Journal of Obstetrics and Gynaecology Canada. 36 (4): 343–348. doi: 10.1016/s1701-2163(15)30611-3 . PMID   24798673.
  30. ↑ "Un antinauséeux à utiliser avec prudence?". 17 April 2014.
  31. ↑ "Health Canada confidentiality pact forces doctor to withhold drug data". CBC Radio. 15 October 2015.
  32. ↑ "Health Canada hands over documents but muzzles doctor | the Star". The Toronto Star. 14 October 2015.
  33. ↑ McCarthy LS (June 1994). "Life After Daubert v. Merrell Dow: Maine as a Case Law Laboratory for Evidence Rule 702 Without Frye". Maine Law Review. 46 (2).
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