Active ingredients: Indomethacin, Caffeine, Prochlorperazine (Prochlorperazine dimaleate)
DIFMETRE 'coated tablets
DIFMETRE 'effervescent tablets
DIFMETRE 'suppositories
DIFMETRE 'low dosage suppositories
Why is Difmetre used? What is it for?
Pharmacotherapeutic group / type of activity
Anti-migraine drugs
Therapeutic indications
Treatment of acute migraine attack with or without aura. It is particularly suitable for the treatment of patients who suffer from nausea and vomiting during the attack.
Treatment of tension headache episodes.
Contraindications When Difmetre should not be used
Hypersensitivity to the active substances or to any of the excipients.
Difmetre should not be used in patients with a history of gastrointestinal bleeding or perforation related to previous active treatments or a history of recurrent peptic ulcer / haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
Indomethacin is contraindicated in patients who have had allergic reactions to indomethacin, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs), in patients with severe heart failure, with mental disorders, in epileptics, in parkinsonians.
Third trimester of pregnancy.
Difmetrè suppositories should not be used in patients who have recently had a rectal bleeding or who suffer from proctitis.
Precautions for use What you need to know before taking Difmetre
The use of Difmetré is reserved for the treatment of crises in progress: it is therefore not recommended to use it continuously. In case of repeated treatment, tests of blood count and liver and kidney function should be performed.
Interactions Which drugs or foods can modify the effect of Difmetre
Tell your doctor if you are being treated with:
- oral cortisones: increased risk of gastrointestinal ulceration or bleeding (see Special Warnings)
- drugs that act on blood clotting (anticoagulants such as warfarin or antiplatelet drugs such as aspirin): NSAIDs can increase the effects of these drugs
- antidepressant drugs (selective serotonin reuptake inhibitors or SSRIs): increased risk of gastrointestinal bleeding (see Special Warnings)
- drugs for the treatment of hypertension (diuretics, ACE inhibitors and angiotensin II antagonists): NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (eg dehydrated patients or elderly patients with impaired renal function), co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to further deterioration of renal function, including possible acute renal failure , generally reversible. These interactions should be considered in patients taking NSAIDs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in elderly patients. Patients should be adequately hydrated and considered. monitoring of renal function after initiation of concomitant therapy.
- anti-inflammatory drugs (including selective COX-2 inhibitors)
- digitalis (heart failure drug): the indomethacin contained in the medicine may increase the plasma levels of digoxin
- lithium (drug for mania): the indomethacin contained in the drug may increase plasma levels of lithium
- anticholinergic drugs: the prochlorperazine contained in the medicine could increase anticholinergic side effects
- medicines for Parkinson's disease: the prochlorperazine contained in the medicine can reduce their effectiveness
- QT prolonging drugs: when neuroleptics such as prochlorperazine are administered concomitantly with QT prolonging drugs the risk of developing heart disease increases (see Special Warnings and Side Effects)
- drugs that cause changes in electrolytes: neuroleptics such as prochlorperazine can interact with these drugs (see Special warnings and side effects)
- medicines for insomnia or anxiety (benzodiazepines): the caffeine contained in the medicine can reduce the sedative and anxiolytic effects of benzodiazepines
- theophylline (drug for asthma): high doses of caffeine can increase plasma levels of theophylline.
Warnings It is important to know that:
Difmetrè contains Indomethacin which falls into the category of NSAIDs, non-steroidal anti-inflammatory drugs.
Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see Dose, method and time of administration and the gastrointestinal and cardiovascular risks below). "Use of Difmetrè should be avoided concomitantly with NSAIDs, including selective COX-2 inhibitors.
Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see Undesirable Effects).
Gastrointestinal bleeding, ulceration and perforation: Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported during treatment with all NSAIDs, at any time, with or without warning symptoms or a previous history of serious gastrointestinal events.
In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see Contraindications), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of NSAIDs. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of aspirin or other drugs that may increase the risk of gastrointestinal events (see below and Interactions).
Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.
Caution should be exercised in patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see Interactions).
When gastrointestinal bleeding or ulceration occurs in patients taking Difmetrè the treatment should be discontinued.
NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Side Effects).
Adequate monitoring and instruction are required in patients with a history of mild to moderate hypertension and / or congestive heart failure as fluid retention and edema have been reported in association with NSAID treatment.
NSAIDs as well as indomethacin may be associated with a modest increased risk of heart attack ("myocardial infarction") or stroke. Any risk is more likely with high doses and prolonged treatments. Do not exceed the recommended dose or duration of treatment.
If the patient has heart problems, or a history of stroke or thinks they may be at risk for these conditions (for example if they have high blood pressure, diabetes or high cholesterol or smoke) they should discuss their therapy with their doctor or pharmacist.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see Undesirable Effects). Patients appear in the early stages of therapy. be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Difmetre should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
Difmetrè contains prochlorperazine which falls into the category of neuroleptics. Use with caution in patients with cardiovascular disease or with a family history of QT prolongation. Avoid concomitant therapy with other neuroleptics.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking the coated tablets.
Pregnancy
The inhibition of prostaglandin synthesis, induced by NSAIDs such as indomethacin, can negatively affect pregnancy and / or embryo / fetal development.
During the first and second trimester of pregnancy, indomethacin should not be administered except in strictly necessary cases.
If indomethacin is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can exhibit:
- the fetus to:
- cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
- renal dysfunction, which can progress to renal failure with oligo-hydroamnios;
- the mother and the newborn, at the end of pregnancy, to:
- possible prolongation of bleeding time, and antiplatelet effect which may occur even at very low doses;
- inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, Difmetrè is contraindicated during the third trimester of pregnancy.
Feeding time
During lactation, the product should only be administered after consulting your doctor and evaluating with him the benefit / risk ratio in your case.
Effects on ability to drive and use machines
DIFMETRÈ can make you drowsy and therefore, after taking DIFMETRÈ, you are advised not to attend to activities that require complete mental attention, such as driving cars or using machines.
Dosage and method of use How to use Difmetre: Dosage
It is recommended to take Difmetrè as soon as possible after the onset of the headache, however the drug is effective even if taken at a later stage.
Difmetrè effervescent tablets: open the tube by pressing upwards on the notch on the cap.
The effervescent tablets must be dissolved in half a glass of plain water. Drink as soon as the dissolution of the tablets is complete.
Adults (ages 18 to 65)
The recommended starting dose is one oral tablet or one rectal suppository at the onset of headache. The pharmaceutical form and dosage should be chosen according to the severity of the symptoms and the individual characteristics of the patient. Suppository formulations. they are particularly suitable for patients with nausea and vomiting.
If there is no response: If there is no improvement in headache within 2 hours after taking the first dose of Difmetrè, a second dose of the same strength taken for the same attack has been shown to be effective in treating headache. Clinical studies show that patients who do not respond to treatment for one headache are likely to respond to treatment for a subsequent attack.
If headache recurs within 24-48 hours: If headache recurs within 24-48 hours after an initial response, a second dose of Difmetrè of the same strength has been shown to be effective in treating relapses.
It is advisable not to exceed the maximum daily dose of 4 suppositories or 8 tablets.
Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see Special warnings).
Children and adolescents (under 18 years of age)
There are no data on the use of Difmetrè in children and adolescents, therefore its use is not recommended in this age group.
Elderly (over 65 years of age)
The safety and efficacy of Difmetrè in patients over 65 years of age have not been systematically evaluated.
Overdose What to do if you have taken too much Difmetre
In case of accidental intake / ingestion of an excessive dose of Difmetrè, notify your doctor immediately or go to the nearest hospital.
- indomethacin such as gastrointestinal or nervous system symptoms
- caffeine such as nausea, vomiting, anxiety, tremors, seizures, rapid heartbeat, arrhythmias, drop in blood pressure, low blood potassium and metabolic lactic acidosis
- prochlorperazine as extrapyramidal symptoms (like Parkinson's disease), which may be accompanied by confusion, sleepiness or agitation, disturbed concentration, seizures or changes in the electrocardiogram.
Treatment is essentially symptomatic and supportive. Gastric lavage is useful, especially if it is prompt. The airways, which could be threatened by muscle dystonia, must be kept clear. In case of hypotension, ventilation must be taken care of. The supine position may have the desired effect; otherwise, slow infusion of noradrenaline or metaraminol or other intramuscular pressures should be given. Do not use epinephrine. Hemodialysis is of no help.
Side Effects What are the side effects of Difmetre
Difmetrè has been administered in clinical studies to over 250 patients who have taken one or two doses within 48 hours and have treated one or two migraine attacks or tension headache episodes. The most common side effects (<3%) were vertigo, dizziness and tremor. The undesirable effects reported in clinical studies with Difmetrè usually appear immediately after taking the drug, are generally mild or moderate and resolve spontaneously within a few hours. they can be minimized by lying on your back and reducing the initial dosage in the next attack. Some of the symptoms reported as side effects may be accompanying migraine symptoms. The undesirable effects listed below are those that in clinical studies were considered related to treatment with Difmetrè, listed by decreasing incidence and system:
Cardiovascular:
Common (> 1/100, <1/10): tachycardia
Auditory and vestibular system:
Common (> 1/100, <1/10): dizziness
Visual apparatus:
Uncommon (> 1/1000, <1/100): visual disturbances
Gastrointestinal:
Common (> 1/100, <1/10): nausea,
Uncommon (> 1/1000, <1/100): vomiting, dyspepsia, gastritis, upper abdominal pain
Systemic:
Uncommon (> 1/1000, <1/100): asthenia, malaise, chills, pain
Infections:
Uncommon (> 1/1000, <1/100): influenza
Nervous system:
Common (> 1/100, <1/10): dizziness, tremor,
Uncommon (> 1/1000, <1/100): paraesthesia, stupor, loss of consciousness, somnolence, tension headache, disturbance in attention
Psychiatric:
Uncommon (> 1/1000, <1/100): agitation, motor restlessness
Respirators:
Uncommon (> 1/1000, <1/100): dyspnoea
Skin and skin appendages:
Uncommon (> 1/1000, <1/100): sweating
Vascular:
Uncommon (> 1/1000, <1/100): hypotension
Other undesirable effects reported during marketing were: arrhythmia, dry mouth, diarrhea, changes in blood count, confusion, skin rash, hypertension. Data from clinical trials and marketing indicate that low dose suppositories have a lower incidence of side effects compared to tablets and suppositories.
The most commonly observed adverse events with indomethacin are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes fatal, may occur, particularly in the elderly (see Precautions for use). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration of indomethacin (see Special Warnings). Gastritis has been observed less frequently. Edema, hypertension and heart failure have been reported in association with NSAID treatment.
NSAIDs as well as indomethacin may be associated with a modest increased risk of heart attack ("myocardial infarction") or stroke. Bullous reactions including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (very rarely) have been reported.
Due to the presence of prochlorperazine, anticholinergic symptoms (constipation, dry mouth, sedation) or extrapyramidal symptoms could theoretically occur; however at doses up to 40 mg per day, prochlorperazine is devoid of significant side effects.
The following side effects have been observed with other drugs of the same class as prochlorperazine (neuroleptics): rare cases of QT prolongation, ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest. Very rare cases of sudden death.
Due to the presence of caffeine, a caffeine hyperstimulation syndrome with agitation, restlessness, insomnia, tremors, palpitations, tachycardia, hypertension may occur. Furthermore, the continued intake of caffeine-containing drugs can lead to a withdrawal reaction, characterized mostly by headache.
The patient is invited to report any undesirable effect not described in the package leaflet to his doctor or pharmacist.
Expiry and Retention
Check the expiration date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after this date.
Effervescent tablets: validity after opening the tube: 2 months.
Keep this medicine out of the reach and sight of children.
The effervescent tablets must be stored at a temperature not exceeding 30 ° C. Keep the tube tightly closed.
Store suppositories at a temperature not exceeding 25 ° C.
Composition and pharmaceutical form
Composition
DIFMETRÈ coated tablets
One coated tablet contains:
Active ingredient: 25 mg indomethacin, 75 mg caffeine, 2 mg prochlorperazine dimaleate.
Excipients: mannitol (E421), colloidal hydrated silica (E551), povidone (E1201), talc (E553b), corn starch, magnesium stearate (E470b), gum arabic, sucrose, white carnauba wax.
DIFMETRÈ effervescent tablets
One effervescent tablet contains:
Active ingredient: 25 mg indomethacin, 75 mg caffeine, 2 mg prochlorperazine dimaleate.
Excipients: anhydrous citric acid (E330), sodium hydrogen carbonate (E500), sorbitol (E420), sodium saccharin (E954), lemon flavoring, macrogol 6 glycerol caprilocaprate, dimethicone (E900)
DIFMETRÈ suppositories
One suppository contains:
Active ingredient: 50 mg indomethacin, 150 mg caffeine, 8 mg prochlorperazine dimaleate.
Excipients: solid semisynthetic glycerides.
DIFMETRÈ low dosage suppositories
One suppository contains:
Active ingredient: 25 mg indomethacin, 75 mg caffeine, 4 mg prochlorperazine dimaleate.
Excipients: solid semisynthetic glycerides.
Pharmaceutical form and content
DIFMETRÈ coated tablets: box of 20 tablets.
DIFMETRÈ effervescent tablets: box of 20 tablets, containing two tubes of 10 tablets each
DIFMETRÈ suppositories: box containing 6 suppositories
DIFMETRÈ low dosage suppositories: box containing 6 suppositories
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DIFMETRÈ
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One coated tablet contains:
Active ingredients: 25 mg indomethacin - 75 mg caffeine - 2 mg prochlorperazine dimaleate.
One effervescent tablet contains:
Active ingredients: indomethacin 25 mg -caffein 75 mg -prochlorperazine dimaleate 2 mg.
One suppository contains:
Active ingredients: indomethacin 50 mg - caffeine 150 mg - 8 mg prochlorperazine dimaleate.
A low dosage suppository contains:
Active ingredients: 25 mg indomethacin - 75 mg caffeine - 4 mg prochlorperazine dimaleate.
For excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Coated tablets, effervescent tablets and suppositories.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of acute migraine attack with or without aura. It is particularly suitable for the treatment of patients who suffer from nausea and vomiting during the attack.
Treatment of tension headache episodes.
04.2 Posology and method of administration
It is recommended to take Difmetrè as soon as possible after the onset of the headache, however the drug is effective even if taken at a later stage.
Difmetrè effervescent tablets: open the tube by pressing upwards on the notch on the cap, take the effervescent tablets after complete dissolution in water.
Adults (ages 18 to 65)
The recommended starting dose is one oral tablet or one rectal suppository at the onset of headache. The pharmaceutical form and dosage should be chosen according to the severity of the symptoms and the individual characteristics of the patient. Suppository formulations. they are particularly suitable for patients with nausea and vomiting.
In case of no answer: If there is no improvement in headache within 2 hours of taking the first dose of Difmetrè, a second dose of the same strength taken for the same attack has been shown to be effective in treating headache. Clinical studies show that patients who do not respond to treatment for one headache are likely to respond to treatment for a subsequent attack.
If the headache comes back within 24-48 hours: If the headache recurs within 24 to 48 hours after an initial response, a second dose of Difmetrè of the same strength has been shown to be effective in treating relapses.
It is advisable not to exceed the maximum daily dose of 4 suppositories or 8 tablets. Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4).
Children and adolescents (under 18 years of age)
There are no data on the use of Difmetrè in children and adolescents, therefore its use is not recommended in this age group.
Elderly (over 65 years of age)
The safety and efficacy of Difmetrè in patients over 65 years of age have not been systematically evaluated.
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Difmetre should not be used in patients with a history of gastrointestinal bleeding or perforation related to previous active treatments or a history of recurrent peptic ulcer / haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
Indomethacin is contraindicated in patients who have had allergic reactions to indomethacin, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs), in patients with severe heart failure, with mental disorders, in epileptics, in parkinsonians.
Third trimester of pregnancy.
Difmetrè suppositories should not be used in patients who have recently had a rectal bleeding or who suffer from proctitis.
04.4 Special warnings and appropriate precautions for use
The use of Difmetré is reserved for the treatment of crises in progress: it is therefore not recommended to use it continuously. In case of repeated treatment, tests of blood count and liver and kidney function should be performed.
Difmetrè contains Indomethacin which falls into the category of NSAIDs, non-steroidal anti-inflammatory drugs.
Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.2 and below on gastrointestinal and cardiovascular risks).
The use of Difmetrè should be avoided concomitantly with NSAIDs, including selective COX-2 inhibitors.
Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.8).
Gastrointestinal bleeding, ulceration and perforation: Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported during treatment with all NSAIDs, at any time, with or without warning symptoms or a previous history of serious gastrointestinal events.
In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of NSAIDs. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of aspirin or other drugs that may increase the risk of gastrointestinal events (see below and section 4.5). . Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. Caution should be exercised in patients taking concomitant medications which could increase the risk of ulceration or bleeding , such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).
When gastrointestinal bleeding or ulceration occurs in patients taking Difmetrè the treatment should be discontinued.
NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).
Adequate monitoring and instruction are required in patients with a history of mild to moderate hypertension and / or congestive heart failure as fluid retention and edema have been reported in association with NSAID treatment.
Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for long-term treatment) may be associated with a modest increased risk of arterial thrombotic events (eg myocardial infarction or stroke).
There are insufficient data to exclude a similar risk for indomethacin.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and / or cerebrovascular disease should only be treated with indomethacin after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (eg hypertension, hyperlipidaemia, diabetes mellitus, smoking).
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). In the early stages of therapy, patients appear to be be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Difmetrè should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity Difmetrè contains prochlorperazine which falls into the category of neuroleptics. Use with caution in patients with cardiovascular disease or with a family history of QT prolongation. Avoid concomitant therapy with other neuroleptics.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take the coated tablets.
04.5 Interactions with other medicinal products and other forms of interaction
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4).
Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to further deterioration of renal function, including possible acute renal failure, usually reversible. These interactions should be considered in patients taking NSAIDs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in elderly patients. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy.
Concomitant use of indomethacin with digoxin or lithium may increase plasma levels of both.
As with all phenothiazines, caution should be used in the concomitant use of prochlorperazine with anticholinergic drugs, for possible increase of anticholinergic side effects, and with drugs for Parkinson's disease, for possible decrease in the efficacy of the latter.
When neuroleptics such as prochlorperazine are administered concomitantly with QT prolonging drugs the risk of developing cardiac arrhythmias increases (see sections 4.4 and 4.8).
Do not administer concomitantly with drugs that cause electrolyte disturbances: neuroleptics such as prochlorperazine can interact with these drugs (see sections 4.4 and 4.8).
Caffeine can reduce the sedative and anxiolytic effects of benzodiazepines. High doses of caffeine can increase plasma levels of theophylline.
In consideration of the fact that Difmetrè contains low dosages of the three active ingredients and is indicated for acute treatment, the appearance of such interactions is however unlikely.
04.6 Pregnancy and lactation
Pregnancy
The inhibition of prostaglandin synthesis, induced by NSAIDs such as indomethacin, can negatively affect pregnancy and / or embryo / fetal development.
Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk has been considered to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and mortality. In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals administered prostaglandin synthesis inhibitors during the organogenetic period.
During the first and second trimester of pregnancy, indomethacin should not be administered except in strictly necessary cases.
If indomethacin is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can exhibit:
the fetus to:
- cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
- renal dysfunction, which can progress to renal failure with oligo-hydroamnios;
the mother and the newborn, at the end of pregnancy, to:
- possible prolongation of bleeding time, and antiplatelet effect which may occur even at very low doses;
- inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, Difmetrè is contraindicated during the third trimester of pregnancy.
Feeding time
Indomethacin, caffeine and prochlorperazine are excreted in breast milk.
Infant exposure can be minimized by avoiding breastfeeding for 24 hours after dosing.
04.7 Effects on ability to drive and use machines
The product can cause drowsiness, subjects who could drive vehicles or wait for operations requiring integrity of the degree of vigilance must be warned.
04.8 Undesirable effects
Difmetrè has been administered in clinical studies to over 250 patients who have taken one or two doses within 48 hours and have treated one or two migraine attacks or tension headache episodes. The most common side effects (vertigo, dizziness and tremor. The side effects reported in clinical studies with Difmetrè usually appear soon after taking the drug, are generally mild or moderate and resolve spontaneously within a few hours. However, Difmetre is not affected by the onset of these effects, which can be minimized by lying on your back and reducing the initial dosage in the next attack. Some of the symptoms reported as side effects may be accompanying symptoms of migraine. The reported side effects of migraine. below are those that in clinical studies were considered related to treatment with Difmetrè, listed according to decreasing incidence and system:
Cardiovascular:
Common (> 1/100, tachycardia
Auditory and vestibular system:
Municipalities (> 1/100,
Visual apparatus:
Uncommon (> 1/1000, visual disturbances
Gastrointestinal:
Municipalities (> 1/100,
Uncommon (> 1/1000, dyspepsia, gastritis, upper abdominal pain Systemic:
Uncommon (> 1/1000, asthenia, malaise, chills, pain
Infections:
Uncommon (> 1/1000, influenza
Nervous system:
Municipalities (> 1/100,
Uncommon (> 1/1000, paraesthesia, stupor, loss of consciousness, somnolence, tension headache, disturbance in attention
Psychiatric:
Uncommon (> 1/1000, motor restlessness
Respirators:
Uncommon (> 1/1000, dyspnoea
Skin and skin appendages:
Uncommon (> 1/1000, sweating
Vascular:
Uncommon (> 1/1000, hypotension
Other undesirable effects reported during marketing were: arrhythmia, dry mouth, diarrhea, changes in blood count, confusion, skin rash, hypertension.
Data from clinical trials and marketing indicate that low dose suppositories have a lower incidence of side effects than tablets and suppositories.
The most commonly observed adverse events with indomethacin are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes fatal, may occur, particularly in the elderly (see Precautions for use).
Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration of indomethacin (see section 4.4). Gastritis has been observed less frequently.
Edema, hypertension and heart failure have been reported in association with NSAID treatment.
Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for long-term treatment) may be associated with a modest increased risk of arterial thrombotic events (eg, myocardial infarction or stroke) ( see section 4.4).
Bullous reactions including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported (very rarely)
Due to the presence of prochlorperazine, anticholinergic symptoms (constipation, dry mouth, sedation) or extrapyramidal symptoms could theoretically occur; however at doses up to 40 mg per day, prochlorperazine is devoid of significant side effects.
The following side effects have been observed with other drugs of the same class as prochlorperazine (neuroleptics): rare cases of QT prolongation, ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest. Very rare cases of sudden death.
Due to the presence of caffeine, a caffeine hyperstimulation syndrome with agitation, restlessness, insomnia, tremors, palpitations, tachycardia, hypertension may occur. Furthermore, the continued intake of caffeine-containing drugs can lead to a withdrawal reaction, characterized mostly by headache.
04.9 Overdose
There have been no reports since marketing of an overdose with Difmetrè. Taking into account the recommended dosage of Difmetrè, an overdose is unlikely.
Symptoms
The clinical manifestations resulting from an acute overdose of indomethacin are not known: the symptoms of toxicity are probably affecting the gastrointestinal tract and the central nervous system.
Overdose of caffeine generally results in low toxicity. Severe caffeine poisoning can lead to nausea, vomiting, anxiety, tremors, convulsions, tachycardia, arrhythmias, hypotension, hypokalaemia, and metabolic lactic acidosis.
Possible overdose effects of prochlorperazine, the low dosage of which, however, makes this occurrence rather unlikely are: extrapyramidal symptoms accompanied by confusion, drowsiness or agitation, concentration disturbances, convulsions or electrocardiographic changes.
Treatment
Treatment is essentially symptomatic and supportive. Gastric lavage is useful, especially if prompted. The airways, which can be threatened by muscle dystonia, must be kept clear. In case of hypotension, ventilation should be taken care of; the position of the body can give the desired effect otherwise administer norepinephrine by slow infusion or metaraminol or other pressors intramuscularly.
Don't use adrenaline. Hemodialysis is of no help.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-migraines
ATC code: N02CX99
Mechanism of action / pharmacology
The three active ingredients of Difmetrè have been shown to have specific pharmacological activities for the treatment of migraine and headache.
Unlike other NSAIDs, indomethacin is chemically related to serotonin and has a specific central analgesic and vasoconstrictive action on the head circulation. Caffeine has a central cholinergic analgesic effect and, in addition to NSAIDs, has been shown to reduce by 40% the dose of NSAID needed to achieve the analgesic effect. Prochlorperazine is a phenothiazine with central antiemetic and analgesic properties of the cholinergic type.
In animal models of migraine, each of the three active substances has been shown to reduce hyperalgesia at doses 10 times lower than analgesic ones. The reduction in hyperalgesia induced by the combination of the three active substances was significantly greater than that induced by the single substances. active. Furthermore, indomethacin and the association of the three active ingredients of Difmetrè have been shown to abolish the central and peripheral sensitization, which occurs during the migraine attack.
05.2 Pharmacokinetic properties
Indomethacin
Indomethacin is rapidly absorbed from the gastrointestinal tract both orally and rectally; bioavailability is almost 100% by mouth and 80-90% by rectal; the blood peak (Tmax) is between 1/2 hour and 2 hours; more than 90% of indomethacin is bound to plasma proteins; the volume of distribution is between 0.34 and 1.57 l / kg; it is metabolised in the liver to inactive metabolites, the elimination half-life (t1 / 2) is 2-8 hours; 60% is excreted in the urine, mainly in the form of glucuronide, and the rest in the faeces.
Caffeine
Caffeine is rapidly and almost completely absorbed both orally and rectally; the Tmax is about 1 hour; 35% of caffeine is bound to plasma proteins; the volume of distribution is 0.53 l / kg; it is completely metabolised in the liver into active metabolites, the main one being paraxanthin; t1 / 2 is 4-5 hours; it is excreted in the urine in the form of l-methyluric acid and l-methylxanthine.
Prochlorperazine
Prochlorperazine is readily absorbed from the gastrointestinal tract; oral bioavailability is low; the Tmax is 1.5-5 hours; the volume of distribution is 12.9-17.7 l / kg; it is extensively metabolised in the liver; the t½ is 6.8-9 hours; it is excreted in the urine and faeces in the form of numerous metabolites.
Association
The pharmacokinetic properties of Difmetrè in healthy subjects are not different from those of the single active ingredients.
In healthy subjects, after single oral administration of Difmetrè, the Tmax was 1.9-1.4-2.4 hours, respectively for indomethacin, caffeine and prochlorperazine.
The t1 / 2 in healthy subjects of a single oral administration of Difmetrè is approximately 6 hours.
05.3 Preclinical safety data
Toxicity studies carried out with the combination of indomethacin, caffeine and prochlorperazine in the same proportions as Difmetrè showed the following results:
Acute toxicity: in the dog, by rectally administering suppositories containing the active ingredients in an amount three times higher than that contained in Difmetrè suppositories, it is not possible to detect acute toxic phenomena, even by administering the maximum possible number of suppositories.
Chronic toxicity: in dogs, a rectal dose equal to 3 times that of humans, is perfectly tolerated both clinically and pathologically for a period of 6 months. A dose equal to 6 times that of humans is capable of inducing lesions in the gastrointestinal tract. A dose equal to 12 times the human dose induces severe gastro-intestinal lesions, which lead to death, in most animals .
Teratogenesis and fetal toxicity: in dogs, a rectal dose of 3 to 6 times that of humans is not teratogenic and does not cause fetal toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
One coated tablet contains:
mannitol (E421), colloidal hydrated silica (E551), povidone (E1201), talc (E553b), corn starch, magnesium stearate (E470b), gum arabic, sucrose, white carnauba wax.
One effervescent tablet contains:
anhydrous citric acid (E330), sodium hydrogen carbonate (E500), sorbitol (E420), sodium saccharin (E954), lemon flavoring, macrogol 6 glycerol caprilocaprate, dimethicone (E900).
One suppository contains:
solid semisynthetic glycerides to taste at 1.5 g.
A low dosage suppository contains:
solid semisynthetic glycerides to taste at 1.5 g.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Coated tablets and suppositories: 5 years.
Effervescent tablets: 3 years. Validity after opening the tube: 2 months.
06.4 Special precautions for storage
The effervescent tablets must be stored at a temperature not exceeding 30 ° C.
Store in the original container tightly closed.
Store suppositories at a temperature not exceeding 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Coated tablets: pack containing a blister of 20 coated tablets.
Effervescent tablets: pack containing 20 effervescent tablets in two polypropylene tubes of 10 tablets each.
Suppositories: package containing 6 suppositories in PVC blisters.
Low dosage suppositories: pack containing 6 suppositories in PVC blisters.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
BGP PRODUCTS S.r.l. - Viale Giorgio Ribotta, 11 -00144 Rome
08.0 MARKETING AUTHORIZATION NUMBER
Coated tablets: AIC 021633021.
Effervescent tablets: AIC 021633045
Suppositories: AIC 021633019.
Low dosage suppositories: AIC 021633033.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Coated tablets: box of 20 tablets: 18-12-71 / 31-05-2010
Effervescent tablets: box of 20 tablets: 30-01-2007 / 31-05-2010
Suppositories: box of 6 suppositories: 21-03-70 / 31-05-2010
Low dosage suppositories: box of 6 suppositories: 28-06-79 / 31-05-2010
