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Donnatal

January 01, 1970

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.

Indication edit

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 edit

Clinical Research with Combinations of Belladonna Alkaloids and Phenobarbital edit

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 edit

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 edit

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]

References edit

  1. ^ a b c Donnatal Tablets Package Insert. Concordia Pharmaceuticals. http://www.donnatal.com/wp-content/uploads/2015/03/Donnatal-Tablets-PI-0315-v3.pdf
  2. ^ a b c 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).

External links edit

  • . Archived from the original on 2008-12-27.

January 01, 1970
donnatal, combination, medication, that, provides, natural, belladonna, alkaloids, specific, fixed, ratio, combined, with, phenobarbital, provide, peripheral, anticholinergic, antispasmodic, action, mild, sedation, manufactured, concordia, pharmaceuticals, iri. 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 1 Indication 2 History 2 1 Clinical Research with Combinations of Belladonna Alkaloids and Phenobarbital 2 2 Donnatal clinical research 2 3 FDA status 3 References 4 External linksIndication editBased 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 editClinical Research with Combinations of Belladonna Alkaloids and Phenobarbital edit 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 edit 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 gt 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 edit 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 References edit a b c Donnatal Tablets Package Insert Concordia Pharmaceuticals http www donnatal com wp content uploads 2015 03 Donnatal Tablets PI 0315 v3 pdf a b c Donnatal Elixir Package Insert Concordia Pharmaceuticals http www donnatal com wp content uploads 2012 02 Donnatal Elixir PI 0415 v1 pdf 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 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 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 Miskimon RM 1954 Report of 700 cases of irritable colon in private practice VA Med Mon 1918 81 3 109 113 PMID 13136900 Kadish AH 1957 Functional disturbances treated with a potent antispasmodic and sedative Am Pract Dig Treat 7 12 2006 2008 PMID 13372950 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 Ezzo JA 1957 Antispasmodic therapy adjunctive prolonged action in gastrointestinal disorders Mo Med 54 11 1053 1054 PMID 13477174 Maly RF 1968 Drug therapy in the management of gastrointestinal complaints J Iowa Med Soc 58 12 1231 1233 PMID 5705309 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 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 Hardman JG Limbird LE Gilman AG Ed Goodman and Gilman s Pharmacological Basis of Therapeutics 10th edition 2001 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 Information provided by the FDA to committee staff RE Drug Efficacy Study Implementation DES program PDF Drugs for human use Drug Efficacy Study Implementation Certain prescription drugs offered for various indications opportunity to affirm outstanding hearing request Guidance for FDA staff and industry marketed unapproved drugs compliance policy guide PDF Donnatal Extended Release Tablet Information Approved drug products with therapeutic equivalance evaluations Orange Book short description Exempt Prescription Products List PDF External links edit Donnatal Extended Release Tablet Information Archived from the original on 2008 12 27 Retrieved from https en wikipedia org w index php title Donnatal amp oldid 1183569675, wikipedia, wiki, book, books, library,

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