Source: Medicines Authority (MT) Revision Year: 2023 Publisher: Viatris Healthcare Limited, Damastown Industrial Park, Mulhuddart, Dublin 15, DUBLIN, Ireland
Rantudil forte is contraindicated in patients:
The use Rantudil forte with concomitant NSAIDs including cyclooxigenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2 as well as gastrointestinal and cardiovascular risk further down).
Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs. These events occurred at any point during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in elderly patients. These patients should start treatment at the lowest available dose.
Combination treatment with protective drugs (e.g. misoprostol or proton pump inhibitors) should be considered (see below and section 4.5) for these patients as well as for patients requiring concomitant treatment with low-dose acetylsalicylic acid (ASA) or other medications that may increase gastrointestinal risk (see section 4.5).
Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.
Caution is advised in patients being treated with concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors used to treat depressive mood disorders, or antiplatelet agents such as ASA (see section 4.5).
Treatment should be discontinued if gastrointestinal bleeding or ulceration occurs in patients taking Rantudil forte.
NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their status may worsen (see section 4.8).
Appropriate monitoring and counselling of patients with hypertension and/or a history of minor to moderately severe decompensated cardiac insufficiency is required, as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trials and epidemiological data suggest that use of certain NSAIDs (especially when used at high doses and in long-term treatment) may be associated with a small increase in the risk for arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data available to exclude such a risk in case of acemetacin.
Patients with uncontrolled hypertension, cardiac insufficiency, acute ischaemic heart disease, peripheral arterial occlusive disease and/or cerebrovascular disease should be treated with acemetacin only after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell’s syndrome) have been reported very rarely in association with the use of NSAIDs (See section 4.8). Patients appear to be at highest risk of these reactions early in the course of treatment, the onset of the reaction occurring in the majority of cases within the first month of treatment. Rantudil forte should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Rantudil forte should be used after careful consideration of the risk/benefit- ratio:
In particular, careful medical supervision is required if you:
Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are very rarely observed. Treatment must be discontinued at the first sign of a severe hypersensitivity reaction after taking Rantudil forte. Medically necessary measures corresponding to the symptoms must be initiated by qualified persons.
Rantudil forte can cause temporary inhibition of platelet aggregation. Patients with bloodclotting disorders should therefore be monitored carefully.
Regular monitoring of hepatic values, renal function and blood count is required for long-term administration of Rantudil forte.
Special caution is advised when administering Rantudil forte prior to surgery.
Prolonged use of analgesics can cause headaches that should not be treated with increased doses of the medicine.
In general, the habitual use of analgesics, especially when several analgesic agents are used in combination, can lead to permanent kidney damage with the risk of kidney failure (analgesic nephropathy).
When using NSAIDs, concomitant consumption of alcohol may increase drug-related side effects, especially those affecting the gastrointestinal tract or the central nervous system.
Long-term treatment with indomethacin, the main metabolite of acemetacin, may occasionally result in changes in the retina (degeneration of the retinal pigment) and corneal opacification. Blurred vision can be a characteristic symptom and requires a thorough ophthalmological examination. As these changes can also be asymptomatic, regular ophthalmological examinations are advisable for patients under long-term treatment with acemetacin. Discontinuation of treatment is recommended if corresponding changes occur.
For information on female fertility, see section 4.6.
Rantudil forte contains lactose and sodium
Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Rantudil forte.
Rantudil forte contains less than 1 mmol (23 mg) of sodium per hard capsule, therefore it is essentially “sodium-free”.
Acemetacin, like other NSAIDs, should be taken with caution together with the following medicinal substances:
Other NSAIDs, including salicylates:
Concomitant administration of several NSAIDs may increase the risk of gastrointestinal ulceration or bleeding due to a synergic effect. Therefore, concomitant use of acemetacin and other NSAIDs should be avoided (see section 4.4).
Digoxin, phenytoin, lithium:
Concomitant administration of Rantudil forte and digoxin (a medicine used to increase cardiac output), phenytoin (a medicine used to treat seizures) or lithium (a medicine used for the treatment of psychiatric disorders) can increase the plasma concentrations of these substances. Monitoring of serum lithium levels is necessary.
Diuretics, ACE inhibitors and angiotensin-II antagonists:
NSAIDs may weaken the effect of diuretic agents and antihypertensive agents. In patients with impaired renal function (such as dehydrated patients or elderly patients), concomitant use of an ACE inhibitor and/or angiotensin-II receptor antagonist and a medicinal product inhibiting cyclooxigenase may lead to further exacerbation of renal function, including the possibility of acute renal failure, which is normally reversible.
Therefore, such a combination should be used with caution, in particular in the elderly. These patients should be encouraged to drink adequate amounts of liquid, and regular monitoring of renal laboratory values should be considered after such combination treatment has been initiated.
Concomitant administration of Rantudil forte and potassium-sparing diuretic agents may lead to hyperkaliaemia. It is therefore necessary to monitor potassium levels.
Glucocorticoids:
Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Platelet-aggregation inhibitors such as acetyl salicylic acid and selective serotonin-reuptake inhibitors (SSRIs):
Increased risk of gastrointestinal bleeding (see section 4.4).
Methotrexate:
Administration of Rantudil forte within 24 hours before or after administration of methotrexate can lead to elevated concentrations of methotrexate and may increase its toxic effects.
Ciclosporine:
Concomitant administration of certain NSAIDs increases the risk of kidney-damaging effects by ciclosporine. This effect cannot be excluded when combining cyclosporin and acemetacin.
Anticoagulant agents:
NSAIDs may enhance the effects of anticoagulant agents such as warfarin (see section 4.4). In case of concomitant treatment, appropriate monitoring of the patient’s blood-clotting status is recommended.
Sulphonylurea:
Interactions between certain NSAIDs and oral antidiabetics (sulphonylureas) have been reported in clinical investigations. To date, no interactions between acemetacin and sulphonylureas have been reported. Nonetheless, as a precautionary measure, monitoring of blood glucose levels is recommended during concomitant use.
Probenecid, sulphinpyrazone:
Medicines containing probenecid or sulphinpyrazone can delay elimination of acemetacin.
Furosemide:
Furosemide can speed up elimination of acemetacin.
Triamterene:
Rantudil forte should not be taken concomitantly with triamterene, as cases of acute renal failure have been observed during ongoing treatment with indomethacin, the main metabolite of acemetacin.
Diflunisal:
Rantudil forte should also not be taken concomitantly with diflunisal as a marked increase in the concentration of indometacin, the main metabolite of acemetacin, is likely. This is associated with an increase in undesirable effects.
Penicillin:
Acemetacin can delay the elimination of penicillin antibiotics.
Particular caution is advised if Rantudil forte is taken together with other centrally acting medicinal products and/or in combination with alcohol (see section 4.4).
Inhibition of prostaglandin synthesis may have a negative effect on pregnancy and/or embryofoetal development. Data from epidemiological studies indicate an increased risk for miscarriage as well as for cardiac malformation and gastroschisis after use of prostaglandin synthesis inhibitors at an early stage of pregnancy. It is assumed that the risk increases with the dose and duration of treatment.
Animal experiments have shown that administration of prostaglandin synthesis inhibitors leads to increased pre-implantation and post-implantation loss as well as to embryo-foetal lethality. Moreover, a higher incidence of various malformations, including cardiovascular malformation, has been reported in animals treated with a prostaglandin synthesis inhibitor during the stage of organogenesis.
From the 20th week of pregnancy onward, acemetacin use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimesters of pregnancy, acemetacin should be administered only if absolutely necessary. If acemetacin is used by a woman who is trying to become pregnant or if the substance is used in the first and second trimesters of pregnancy, the dose should be kept as low as possible and the duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to acemetacin for several days from gestational week 20 onward.
Acemetacin should be discontinued if oligohydramnios or ductus arteriosus constriction are found.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may:
Therefore, acemetacin is contraindicated in the third trimester of pregnancy.
Small quantities of the active ingredient acemetacin and its metabolites pass into breast milk. Therefore, use during the breastfeeding period should be avoided.
As with other medications known to inhibit cyclooxygenase/prostaglandin synthesis, administration of Rantudil forte may impair fertility and is therefore not recommended for women who intend to become pregnant. In case of women who have difficulty in becoming pregnant or in women undergoing infertility investigations, discontinuation of Rantudil forte should be considered.
Higher doses of Rantudil forte can cause side effects involving the central nervous system, such as fatigue and dizziness. This may impair the ability to react in individual cases and therefore impair the ability to drive and/or operate machinery. This applies to a greater extent in combination with alcohol.
The following classifications are used to indicate the frequency of adverse reactions: Very common >1/10, Common >1/100 to <1/10, Uncommon >1/1,000 to <1/100, Rare >1/10,000 to <1/1.000, Very rare <1/10,000, Unknown Frequency cannot be estimated from the available data.
It must be considered that the following side effects are mainly dose-dependent and may vary inter-individually.
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed.
In particular, the risk of occurrence of gastrointestinal bleeding depends on the dose range and the duration of treatment.
Oedema, hypertension and cardiac failure have been reported with concomitant NSAID treatment.
Clinical trials and epidemiological data suggest that the use of certain NSAIDs (especially when used at high doses and in long-term treatment) may be associated with a small increase in the risk for arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Very rare: palpitations, pectanginous disorders, cardiac failure.
Very rare: haemolytic anaemia, dyshaematopoiesis (anaemia including aplastic anaemia, leucopenia, agranulocytosis, thrombocytopenia). Initial symptoms may include: fever, sore throat, superficial lesions in the mouth, flu-like symptoms, severe fatigue, epistaxis and cutaneous haemorrhage.
In these cases, use of the medicinal product must be discontinued immediately and a doctor must be consulted. Self-medication with analgesics and antipyretics should be avoided.
Patients undergoing long-term treatment should have their blood counts monitored at regular intervals.
An influence on thrombocyte aggregation, as well as increased haemorrhagic diathesis is possible.
Common: central nervous disorders such as headache, sleepiness, drowsiness and dizziness.
Very rare: sensibility disorders, muscular asthenia, hyperhidrosis, taste disorders, impaired memory, sleep disorders, seizures.
Administration of Rantudil forte may intensify the symptoms of epilepsy and Parkinson’s disease.
Uncommon: occurrence of double vision; pigment degeneration of the retina and corneal opacification have been reported during long-term treatment with indomethacin, the main metabolite of acemetacin. Blurred vision may be a typical symptom of this (see section 4.4).
Very rare: tinnitus and temporary hearing loss.
Very common: gastrointestinal disorders such as nausea, vomiting, abdominal pain, diarrhoea and minor haemorrhage from the gastrointestinal tract which, in exceptional cases, can cause anaemia.
Common: dyspepsia, flatulence, abdominal cramps, loss of appetite and gastric or duodenal ulcers (sometimes accompanied by bleeding and perforation). Uncommon: bloody vomiting, blood in the stool or bloody diarrhoea.
Very rare: inflammation of the oral mucosa, inflammation of the tongue, oesophageal lesions, discomfort in the lower abdomen (e.g. unspecified bleeding and inflammation of the colon), exacerbation of Crohn’s disease or ulcerative colitis, constipation, formation of intestinal diaphragm-like strictures, inflammation of the pancreas.
The patient must be instructed to discontinue the medication product and to consult a doctor immediately in case of any severe pain in the upper abdomen and/or the occurrence of meleana or haematemesis.
Uncommon: development of oedema (e.g. peripheral oedema), especially in patients with hypertension and/or impaired renal function.
Very rare: micturition disorders, increase in blood urea, acute renal insufficiency, proteinuria, haematuria or renal damage (interstitial nephritis, nephrotic syndrome, papillary necrosis). Therefore, the patient’s renal function should be checked at regular intervals.
Uncommon: hair loss.
Very rare: eczema, enanthema, erythema, photophobia, minor and extensive cutaneous bleeding (also allergy-related), exfoliative dermatitis and rash with bullous eruption, which may also take a grave course such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome).
Very rare: hyperglycosaemia and glucosuria.
In very rare cases, exacerbation of inflammation caused by infection (e.g. development of necrotising fasciitis) has been described in a temporal relationship with the systemic use of NSAIDs. This may be associated with the mechanism of action of NSAIDs. Therefore, patients are advised to seek immediate medical attention if any symptoms of infection appear or worsen while taking Rantudil forte. A check should be made to ascertain whether there is an indication for an anti-infectious/antibiotic treatment.
Very rare: hypertension.
Common: hypersensitivity reactions, such as rash and itching.
Uncommon: hives.
Very rare: severe general hypersensitivity reactions. These may manifest themselves as: oedema of the face and eyelids, swollen tongue, internal laryngeal oedema with stenosis of the airways (angioneurotic oedema), respiratory distress that may lead to an asthma attack, tachycardia, fall in blood pressure leading to life-threatening shock.
Immediate medical attention is required if the patient experiences any of these symptoms, which may occur as early as the first use of this medicinal product.
Very rare: allergy-related vasculitis and pneumonitis.
Common: elevated hepatic enzyme levels in the blood (serum transaminases).
Uncommon: Hepatic damage (hepatitis with or without icterus, very rarely fulminant, and at times without prior symptoms).
The patient’s liver values should therefore be monitored at regular intervals.
Very rare: vaginal bleeding.
Common: agitation.
Rare: irritability.
Very rare: psychiatric disorders, disorientation, anxiety, nightmares, tremors, psychoses, hallucinations, depression and transitory loss of consciousness ranging up to coma. Administration of Rantudil forte may intensify the symptoms of pre-existing psychiatric illnesses.
Post-authorisation reporting of suspected adverse drug reactions is of great importance and enables continuous monitoring of the risk/benefit ratio of the medication. Healthcare professionals are asked to report any suspected adverse reactions to the ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.
Not applicable.
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