Introduction
Materials and methods
Results
Evaluation of comparison studies of prokinetics and HMPs: clinical studies for FD and IBS
Medicinal products studied | Study type | Study characteristics | Jadad score of trial quality | HMP with RCTs in FD and IBS | Ref |
---|---|---|---|---|---|
STW 5, metoclopramide | Randomized controlled, single blind study in FGID | Multicenter single-blinded clinical trial in 77 patients with functional gastroenteropathy. Metoclopramide liquid vs. STW 5 liquid, 2 weeks. End points: GI symptoms including fullness, stomach cramps and heartburn; tolerability | 2 | Yesa
| [3] |
STW 5, metoclopramide | Retrospective epidemiological cohort study in FD | Multicenter, retrospective, pharmacoepidemiological cohort study in 961 patients with functional dyspepsia. End points: Number of symptom free patients after treatment, days of inability to work | n.a. | Yesa
| [4] |
STW 5, STW 5-II, cisapride | Double-blind, randomized controlled clinical trial in FD | Randomized controlled clinical trial in 183 patients with dysmotility type of functional dyspepsia. Double-dummy design. 4 weeks treatment, 6 months follow-up. End point: gastrointestinal symptom score (GIS) [5] | 5 | Yesa
| [6] |
Combination of peppermint and caraway oil, cisapride | Double-blind, randomized controlled clinical trial in FD | Randomized controlled clinical trial in 120 patients with functional dyspepsia. Double-dummy design. 4 weeks treatment. End point: pain score | 5 | No | [31] |
Rikkunshito, domperidone | Open, randomized trial in FD | Open clinical trial in 27 patients over 4 weeks. End point gastrointestinal symptom rating scale (GSRS) | 2 | No | [32] |
Hewei xiaopi capsules, domperidone | Open, randomized trial in FD | Open clinical trial in 63 patients over 4 weeks. End point: FD symptoms | 1 | No | [33] |
Sinisan (modified), cisapride | Open, randomized trial, IBS | Open clinical trial in 47 patients over 8 weeks. End point: IBS symptom scoring | 1 | No | [34] |
Clinical efficacy and safety
Safety related sections from the SPC | STW 5 | Metoclopramide | Domperidone |
---|---|---|---|
Field of application
| For the treatment of functional and motility related gastrointestinal diseases such as functional dyspepsia and irritable bowel syndrome as well as for the supportive treatment of gastritis. These diseases manifest predominantly in complaints of stomach pain, feeling of fullness, bloating, gastro-intestinal cramps, nausea and heartburn | Prevention of delayed chemotherapy induced nausea and vomiting Prevention of radiotherapy induced nausea and vomiting Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting Metoclopramide can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine | For the treatment of the symptoms nausea and vomiting in adults and adolescents with an age of more than 12 years and a body weight of 35 kg at minimum |
Duration of use
| Basically, there is no restriction of the duration of use. The duration of use is determined by the form, severity and course of the disease | The maximum recommended duration of use is 5 days | As a rule, the maximum duration of use should not exceed one week |
Contraindication
| Hypersensitivity against the active substances Children below 3 years, due to the lack of sufficient data | Hypersensitivity against one of the constituents – Gastrointestinal bleeding, mechanical obstruction or gastrointestinal perforation, where a stimulation of motility is a risk – Phaeochromocytoma – Neuroleptic or metoclopramide triggered tardive dyskinesia – Epilepsy – Parkinson disease – Combination with levodopa or dopaminergic agonists – Known history of methamoglobinamia – Use in children below 1 year due to the enhanced risk of extrapyramidal diseases | – Hypersensitivity against one of the constituents – Prolactinoma – Disturbance of hepatic function – Prolonged QTc interval, electrolyte disturbances or congestive cardiac insufficiency – Concomitant use with drugs leading to prolonged QT, or with strong CYP3A4 inhibitors – Gastrointestinal bleedings, mechanical obstruction or gastrointestinal perforation where a stimulation of motility is a risk |
Special warnings and safety measures
| In case that symptoms persist or in case of lack of success of treatment for more than a week or in case symptoms worsen, a medical doctor should be consulted for excluding organic causes Generally, in children below 6 years, in case of abdominal pain a medical doctor should be consulted |
Neurological diseases:
Extrapyramidal diseases (usually reversible) Tardive dyskinesia (especially after prolonged use) Malign neuroleptic syndrome Symptoms of Parkinson disease can worsen.
Methemoglobinemia
Cardiac diseases:
Care is needed in prolonged QTc interval, electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) or congestive cardiac insufficiency, as well as with concomitant use with drugs leading to prolonged QT time
Functional disturbances of liver and kidney:
Reduction of dose needed |
Functional disturbances of kidney:
Reduce dosing frequency and dose
Cardiovascular effects:
Very rarely: Prolongation of QT interval and torsade de pointes in predisposed patients Enhanced risk of severe ventricular arrhythmias or sudden cardiac death, predominantly in high doses and predisposed patients with prolonged QTc interval, electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) or congestive cardiac insufficiency, as well as with concomitant use of drugs leading to prolonged QT time Concomitant use with Levodopa can lead to increased plasma concentrations of levodopa |
Interactions with other drugs and other interactions
| None known |
Contraindicated combinations:
Concomitant use of levodopa or dopaminergic agonists
Combination to be avoided
Ethanol
Take care when combining with
Anticholinergic drugs, morphine derivatives, anxiolytics, sedative H1 antihistaminics, antidepressants, barbiturates, clonidine, neuroleptics, serotonergic drugs, digoxin, ciclosporin, mivacurium and suxamethonium, strong CYP2D6 inhibitors |
Combinations to be avoided:
Concomitant use of antacids or antisecretory drugs Concomitant use with drugs which are metabolized via CYP3A4 (e. g., ketoconazole, erythromycine) leads to enhanced plasma levels of domperidone
Contraindicated combinations:
Drugs leading to prolonged QT times – Antiarrhythmics class IA (e. g., disopyramid, hydrochinidine, chinidine) – Antiarrhythmics class III (e. g. amiodarone, dofetilide, dronedaron, ibutilide, sotalo). – Certain antipsychotics (e. g., haloperidol, pimozide, sertindole) – Certain antidepressants (e. g., citalopram, escitalopram) – Certain antibiotics (e. g., erythromycine, levofloxacine, moxifloxacine, spiramycine) – Certain antimycotics (e. g., pentamidine) – Certain antimalaria drugs (especially halofantrine, lumefantrine) – Certain gastrointestinal drugs (e. g., cisapride, dolasetrone, prucalopride) – Certain antihistaminics (e. g., mequitazine, mizolastine) – Certain anticancer drugs (e. g., toremifen, vandetanib, vincamin) – Certain other drugs (e. g., pepridil, diphemanil, methadone) Strong CYP3A4 inhibitors, e. g., – Protease inhibitors – Systemic azole antimycotics – Some macrolides (erythromycine, clarithromycine, telithromycine)
Combinations not recommended
Moderate CYP3A4 inhibitors (e. g. diltiazem, verapamil, makrolides)
Take care when combining with
– Drugs inducing bradycardia or hypopotassemia as well as the following macrolides: azithromycine, roxithromycine – Ketoconazole (prolongation of QTc, interactions) – Levodopa (interaction) |
Impairment of the ability to drive and to use machines | None | Somnolence, drowsiness, dizziness, dyskinesias and dystonias impairing the ability to drive and to use machines | None or only negligible influence |
Adverse events | |||
Very frequent |
–
| – Somnolence |
–
|
Frequent |
–
| – Diarrhea – Asthenia – Extrapyramidal diseases (especially in children and young adults and in case of overdose), parkinsonism, akathisia – Depression – Hypertension | – Dryness of mouth |
Occasionally |
–
| – Bradycardia – Amenorrhea, hyperprolactinemia – Hypersensitivity – Dystonia, dyskinesia, impaired consciousness – Hallucination – Confusion | – Anxiety, loss of libido – Somnolence, headache – Diarrhea – Exanthema, pruritus – Galactorrhea, breast pain and -tension – Asthenia |
Rare |
–
| – Galactorrhea – Cramps | – |
Very rare | – Hypersensitivity reactions (as e. g., exanthema, pruritus, dyspnea) | – | – |
Unknown |
–
| – Methemoglobinemia, sulfhemoglobinemia – Cardiac arrest, atrioventricular blockage, QT prolongation, torsade de pointes – Gynecomastia – Anaphylactic reaction (including anaphylactic shock) – Tardive dyskinesia, which may be irreversible, malign neuroleptic syndrome – Acute hypertension in patients with phaeochromocytoma | – Allergic hypersensitivity (including anaphylactic shock) – Agitation, nervousness – Oculogyric crisis – Ventricular arrhythmias, prolongation of QTc time, torsade de pointes, sudden cardiac death – Urticaria, angioedema – Urine retention – Gynecomastia, amenorrhea – Abnormal liver function tests, hyperprolactinemia – Acathisia – Depression, – Extrapyramidal side effects, cramps, agitation (mainly in children) |
Overdose | The acute oral toxicity studies in different animal species and long standing therapeutic experience in patients did not give hints on intoxications | Extrapyramidal diseases, somnolence, confusion, hallucination, cardiac and respiratory arrest | Symptoms of overdose were mainly observed in children: Agitation, change of consciousness, cramps, disorientation, somnolence, extrapyramidal reactions |