Donnatal

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Donnatal is a combination medication that provides natural belladonna alkaloids in a specific fixed ratio combined with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation. [1] [2] Donnatal is manufactured for Concordia Pharmaceuticals by IriSys, LLC. It is available as tablets [1] and 5 mL elixir. [2] Active ingredients are listed as: phenobarbital (16.2 mg), hyoscyamine sulfate (0.1037 mg), atropine sulfate (0.0194 mg), and scopolamine hydrobromide (0.0065 mg). The latter two ingredients are found in plants of the family Solanaceae, such as belladonna.

Contents

Indication

Based on a review of this drug by the National Academy of Sciences–National Research Council and/or other information, FDA has classified the indications as follows: "possibly" effective: For use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. May also be useful as adjunctive therapy in the treatment of duodenal ulcer. [1] [2]

History

Clinical Research with Combinations of Belladonna Alkaloids and Phenobarbital

Clinical studies have been performed on different combinations of belladonna alkaloids and phenobarbital over the last 70 years. For example, Steigmann et al. [3] evaluated a combination of 0.25 mg belladonna alkaloids and 50 mg phenobarbital on gastrointestinal symptoms in 93 patients. The population included 33 IBS patients. Eighteen out of 33 patients reported complete relief of symptoms and 13 reported fair response with partial relief within 24 hours. Only 2 IBS patients reported no response. A small assessment of sustained release of 0.4 mg belladonna alkaloids and ~60 mg phenobarbital (1 grain) was performed in patients with functional GI disorders (i.e., gastric hyperacidity, dyspepsia, pyrosis, gas pains and epigastric distress. [4] Overall, 23 of 25 patients reported complete or significant relief of symptoms. Hock also examined the effect of 0.25 mg belladonna alkaloids and 50 mg phenobarbital sustained release formulation in 82 clinical practice patients with various gastrointestinal disturbances including “functional distress” over 27 months. Of the 82 total patients, 33 patients reported a 50-75% and 20 reported a 75-100% improvement. There were specific reports of improvements in pain and bowel habits in over half of the patients.

One of the earliest randomized double-blind clinical trials of belladonna alkaloids + phenobarbital was in 1959 by Lichstein et al. [5] The study involved 75 patients with unstable bowel (whose symptoms are typical or similar to a current diagnosis of IBS) to investigate the combination therapy of an anticholinergic with the addition of phenobarbital against placebo over 15 months. Of these patients, 20 were treated with placebo, 43 were treated with 50 mg phenobarbital in combination with 0.25 mg Belladonna alkaloids, and 12 received both therapies (patients who lacked a response were switched therapy). Of those receiving the belladonna alkaloids / phenobarbital only, 75.6% reported a mean improvement (2+ or better) in all categories. Among the placebo patients only, only 29.8% reported mean improvement in symptoms. When improvement was clinically assessed, 69% of belladonna alkaloids/phenobarbital patients were reported to improve compared to 24% of placebo patients. For the 12 patients who were switched therapies, it was found that they originally were given placebo and switched to treatment therapy. While on placebo, 11.1% of patients reported a mean improvement, whereas 55.5% reported mean improvement on treatment therapy. The authors noted that the response for patients on placebo was rather quick with immediate effects. Further, they noted that among patients with diarrhea, 100% reported an improvement while 53.2% of those with constipation reported an improvement. In several patients with constipation, fiber and laxatives also were provided. In patients where constipation was the chief complaint, the authors noted that they failed to respond.

Several office-belladonna alkaloids ed case series also presented positive outcomes for almost 1,000 patients on the effect of belladonna alkaloids and phenobarbital formulations in irritable colon, other functional disorders, and gastric/duodenal. [6] [7] [8] [9] [10]

Donnatal clinical research

A. H. Robins developed and began marketing Donnatal® in the 1940s. Two studies have been performed over the years specifically with the Donnatal® formulation. Steigmann and Kaminski [11] examined the antisecretory effect of 0.1296 mg belladonna alkaloids + 16.2 mg phenobarbital (Donnatal®) in peptic ulcer patients, motility in a subgroup of patients and clinical effects in all patients (N =176). Of the IBS patients (n =66), a reported good response with complete relief was found in 53% of male patients and 58% of female patients. Fair response with partial improvement was noted in 37% of male patients and 34% of female patients. No response was reported in 10% of male and 8% of female IBS patients. There were few side effects noted with 8% reporting dry mouth. Dosages were reduced in patients who reported drowsiness (10%) as well as 1 patient who reported visual disturbance. Otherwise, the formulation was well tolerated.

Donnatal also is a common component of a GI cocktail used in emergency rooms. In 1976, Donnatal was one of the 25 most widely prescribed drugs in the U.S. [12] It has since been displaced by H2 antagonists and proton pump inhibitors, which are more effective and lack many of the adverse effects of phenobarbital. [13]

A four-week multicenter, randomized placebo-controlled trial by Turner et al. [14] compared Donnatal® tablets (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg and phenobarbital - 16.2 mg) to belladonna alkaloids alone (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg), phenobarbital alone (16.2 mg) and placebo. The intent-to-treat population of 204 IBS patients was evaluated for pain (cramping), nighttime and daytime pain severity, bowel movement frequency, and with a clinician global evaluation of improvement in response to treatment. The response for improvement of pain was mixed for all groups after 1 day. After 1 day, patients exhibited significant improvement in day and night pain as well as clinician global evaluation when taking Donnatal® tablets and belladonna alkaloids, but the phenobarbital group also was statistically better for day and night pain, and the placebo group for day pain. Females taking Donnatal® tablets were 4 times more likely to experience weeks free of daytime pain compared to phenobarbital alone and twice as likely to experience weeks free of nighttime pain compared to belladonna alkaloids. Only the phenobarbital group demonstrated a significant change in pain type compared to belladonna alkaloids at the end of the study with an approximate 48% response rate. Patients on Donnatal® tablets, belladonna alkaloids, and placebo all had non-significant (p > 0.149) shifts to dull pain, 39.5%, 52.3%, and 40.4%, respectively compared to belladonna alkaloids eline. Males also showed a greater response for pain free-weeks on phenobarbital in comparison to Donnatal® tablets. All groups demonstrated an improvement in bowel movement frequency.

FDA status

Donnatal® is considered part of the DESI drug category and currently is listed as one of 14 drugs still under evaluation by the FDA. [15] In response to FDA questions about Donnatal® efficacy, A. H. Robins Co. filed abbreviated new drug applications for Donnatal® tablets (ANDA 86-676), capsules (ANDA 86-677), and Elixir (ANDA 86-661). [16] These ANDAs, with the exception of the capsule formulation, are still in force today and the FDA has not changed the review status of Donnatal® as being conditionally approved for its indication.

On September 29, 2011, the FDA issued new guidance with regard to the DESI category. [17] This effectively disallowed any new DESI formulations to enter the market. The FDA also has stated that DESI drugs do not have any therapeutic equivalent drugs listed in the “Orange Book”. [18] In their description of therapeutic equivalence, the FDA specifically cites Donnatal®. Therefore, any so-called generic drugs on the market with similar formulation to DESI drugs, are considered illegal drugs as the FDA has not reviewed their composition or therapeutic equivalence.

Donnatal, although containing phenobarbital, is exempt from the Controlled Substances Act due to the belladonna alkaloids present in the formulation. [19]

Related Research Articles

<i>Atropa belladonna</i> Species of toxic flowering plant in the nightshade family.

Atropa belladonna, commonly known as belladonna or deadly nightshade, is a toxic perennial herbaceous plant in the nightshade family Solanaceae, which also includes tomatoes, potatoes, and eggplant (aubergine). It is native to Europe, North Africa, and Western Asia. Its distribution extends from Great Britain in the west to western Ukraine and the Iranian province of Gilan in the east. It is also naturalised or introduced in some parts of Canada and the United States.

Irritable bowel syndrome Functional gastrointestinal disorder

Irritable bowel syndrome (IBS), referred to previously as spastic or nervous colon, and spastic bowel, is a functional gastrointestinal disorder characterized by a group of symptoms accompanied together that include abdominal pain and changes in the consistency of bowel movements. These symptoms occur over a long time, often years. It has been classified into four main types depending on whether diarrhea is common, constipation is common, both are common (mixed/alternating), or neither occurs very often. IBS negatively affects quality of life and may result in missed school or work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS. IBS does not lead to malabsorption.

An antispasmodic is a pharmaceutical drug or other agent that suppresses muscle spasms.

Alosetron Medication

Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only.

Tegaserod Medication

Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.

Renzapride

Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors.

Butabarbital Chemical compound

Butabarbital is a prescription barbiturate sleep aid and anxiety medication. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia, relieving general anxiety and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital. Butabarbital can be hydrolyzed to Valnoctamide.

Rifaximin Antibiotic medication

Rifaximin, sold under the brand name Xifaxan and Zaxine (Canada) among others, is an antibiotic medication used to treat travelers' diarrhea, irritable bowel syndrome, and hepatic encephalopathy. It has poor absorption when taken by mouth.

Chlordiazepoxide/clidinium bromide is a fixed-dose combination medication used to treat peptic ulcers, irritable bowel syndrome (IBS), and gastritis. It contains chlordiazepoxide and clidinium bromide. It helps relieve stomach spasms, abdominal cramps, and anxiety related to gastric disorders. Librax is a fixed ratio of these two medications and, as such, is not typically prescribed with an accompanying dosage, but rather directions on how many capsules to take per day. It comes in a capsule taken by mouth, usually three or four times daily, before meals and at bedtime. Chlordiazepoxide is an anti-anxiety medication belonging to the benzodiazepine class. Its use in IBS is thought to be due to its calming ability for patients that have IBS symptoms that are worsened by anxiety. Clidinium bromide is a synthetic quaternary ammonium antimuscarinic, a sub-class of a family of drugs known as anticholinergics. It treats IBS by decreasing gastrointestinal motility.

Eperisone

Eperisone is an antispasmodic drug.

Mebeverine Chemical compound

Mebeverine is a drug used to alleviate some of the symptoms of irritable bowel syndrome. It works by relaxing the muscles in and around the gut.

Lubiprostone Medication used for constipation

Lubiprostone is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

Solabegron is a drug which acts as a selective agonist for the β3 adrenergic receptor. It is being developed for the treatment of overactive bladder and irritable bowel syndrome. It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes.

Alverine is a drug used for functional gastrointestinal disorders. Alverine is a smooth muscle relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the gut and uterus.

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Olaparib Chemical compound (cancer therapy drug)

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Velusetrag Chemical compound

Velusetrag (INN, USAN; previously known as TD-5108) is an experimental drug candidate for the treatment of gastric neuromuscular disorders including gastroparesis, and lower gastrointestinal motility disorders including chronic idiopathic constipation and irritable bowel syndrome. It is a potent, selective, high efficacy 5-HT4 receptor serotonin agonist being developed by Theravance Biopharma and Alfa Wassermann. Velusetrag demonstrates less selectivity for other serotonin receptors, such as 5-HT2 and 5-HT3, to earlier generation 5-HT agonists like cisapride and tegaserod.

Crofelemer

Crofelemer is an antidiarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy. Other possible uses include diarrhea in children, acute infectious diarrhea, and diarrhea in patients with irritable bowel syndrome. It is a purified oligomeric proanthocyanidin from "dragon's blood", the sap of the South American tree Croton lechleri.

Eluxadoline Chemical compound

Eluxadoline, sold under the brand names Viberzi and Truberzi, is a medication taken by mouth for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D). It was approved for use in the United States in 2015. The drug originated from Janssen Pharmaceutica and was developed by Actavis.

Olorinab Chemical compound

Olorinab (APD371) is a drug being developed by Arena Pharmaceuticals for the treatment of gastrointestinal pain associated with Crohn's disease and irritable bowel syndrome. It acts as a potent and selective cannabinoid CB2 receptor agonist and is claimed to be orally active and peripherally selective. Initial Phase IIa exploratory clinical trials have been successful in patients suffering from quiescent Crohn's disease. Arena initiated the Phase IIb Captivate trial in late July 2019 in patients suffering from irritable bowel syndrome related pain, in constipation and diarrhea predominant sub-types. The Phase IIb trial is expected to enroll 240 participants between the ages of 18 to 70.Three doses of 10 mg, 25 mg, and 50 mg are being tested against Placebo in a 3:4 prescription ratio with a Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) masking layout.

References

  1. 1 2 3 Donnatal Tablets Package Insert. Concordia Pharmaceuticals. http://www.donnatal.com/wp-content/uploads/2015/03/Donnatal-Tablets-PI-0315-v3.pdf
  2. 1 2 3 Donnatal Elixir Package Insert. Concordia Pharmaceuticals. http://www.donnatal.com/wp-content/uploads/2012/02/Donnatal-Elixir-PI-0415-v1.pdf
  3. ↑ Steigmann F, Kaminski L, Nasatir S (1959). "Clinical-experimental evaluation of a prolonged-acting antispasmodic-sedative". Am J Dig Dis. 4 (7): 534–548. doi:10.1007/BF02231964. PMID   13661136. S2CID   9243621.
  4. ↑ Santor D (1957). "Treatment of functional gastric distress with a sustained release belladonna-phenobarbital combination". J Med Soc NJ. 54 (2): 53–55. PMID   13406490.
  5. ↑ Lichstein J, Mayer JD (1959). "Drug therapy of the unstable bowel (irritable bowel): a 15-mionth double blind clinical study in 75 cases of response to a prolonged-acting belladonna alkaloid-phenobarbital mixture or placebo". J Chronic Dis. 9 (4): 394–404. doi:10.1016/0021-9681(59)90059-1. PMID   13641369.
  6. ↑ Miskimon RM (1954). "Report of 700 cases of irritable colon in private practice". VA Med Mon 1918. 81 (3): 109–113. PMID   13136900.
  7. ↑ Kadish AH (1957). "Functional disturbances treated with a potent antispasmodic and sedative". Am Pract Dig Treat. 7 (12): 2006–2008. PMID   13372950.
  8. ↑ Backenstoe GS (1957). "A sustained release belladonna phenobarbital combination in the treatment of gastrointestinal disorders". PA Med J (1928). 60 (8): 983–985. PMID   13452712.
  9. ↑ Ezzo JA (1957). "Antispasmodic therapy; adjunctive prolonged-action in gastrointestinal disorders". Mo Med. 54 (11): 1053–1054. PMID   13477174.
  10. ↑ Maly RF (1968). "Drug therapy in the management of gastrointestinal complaints". J Iowa Med Soc. 58 (12): 1231–1233. PMID   5705309.
  11. ↑ Steigmann F, Kaminski L (1956). "Belladonna alkaloid-sedative mixture. Effects on gastric acidity and motility". Am J Dig Dis. 1 (4): 174–189. doi:10.1007/BF02233476. PMID   13302192. S2CID   10768406.
  12. ↑ Knapp DE, Crosby DL, Brandon BM, Knapp DA (May 1978). "Can pharmacists influence drug prescribing? A look at eight of the top 25 drug products for 1976". Am J Hosp Pharm. 35 (5): 593–4. PMID   655185.
  13. ↑ Hardman JG, Limbird LE, Gilman, AG, Ed., Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th edition(2001)
  14. ↑ Turner RR, Rahilly-Tierney C, Cowan D, Scranton R, Peura D (2014). "Belladonna Alkaloid-Phenobarbital (Donnatal) Effective for Treating IBS Symptoms". J Gastro Hepato. 1 (2): 0101:1–6.
  15. ↑ "Information provided by the FDA to committee staff. RE: Drug Efficacy Study Implementation (DES) program" (PDF).
  16. ↑ "Drugs for human use; Drug Efficacy Study Implementation; Certain prescription drugs offered for various indications; opportunity to affirm outstanding hearing request".
  17. ↑ "Guidance for FDA staff and industry marketed unapproved drugs – compliance policy guide" (PDF).
  18. ↑ "Donnatal Extended Release Tablet Information Approved drug products with therapeutic equivalance evaluations (Orange Book) short description".
  19. ↑ "Exempt Prescription Products List" (PDF).
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