Ambit solution for injection 30 mg/ml ampoule 1 ml No. 10

Instructions Ambit solution for injection 30 mg/ml ampoule 1 ml No. 10

Composition

active ingredient: ketorolac;

1 ml of solution contains ketorolac trometamol 30 mg;

Excipients: ethanol 96%, sodium chloride, diluted hydrochloric acid, sodium hydroxide, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear colorless or pale yellow liquid.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. ATC code M01A B15.

Pharmacological properties

Pharmacodynamics

Ketorolac trometamol is a potent nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity. It is not an opioid and has no known effects on opioid receptors. Its mechanism of action is to inhibit the cyclooxygenase enzyme system, thereby inhibiting prostaglandin synthesis. It exhibits minimal anti-inflammatory activity at analgesic doses.

Pharmacokinetics

Intramuscular administration. After intramuscular administration of ketorolac trometamol, it is rapidly and completely absorbed, with a mean peak plasma concentration of 2.2 μg/ml, reached on average 50 minutes after a single 30 mg dose. The effect of age, renal and hepatic function on the terminal plasma half-life and mean total clearance is shown in the table below (estimated after a single 30 mg intramuscular dose of ketorolac).

Intravenous administration. After a single intravenous dose of 10 mg ketorolac trometamol, the mean peak plasma concentration reached 2.4 μg/mL at a mean of 5.4 minutes after dosing, with a terminal plasma half-life of 5.1 hours, a mean volume of distribution of 0.15 L/kg, and a total plasma clearance of 0.35 mL/min/kg.

The pharmacokinetics of ketorolac in humans after single or multiple administrations are linear. Steady-state plasma concentrations are achieved after dosing every 6 hours for one day. Clearance is not altered with chronic dosing. The primary route of elimination of ketorolac and its metabolites is renal: 91.4% (on average) of the administered dose is recovered in the urine and 6.1% (on average) is excreted in the feces.

More than 99% of ketorolac binds to plasma proteins over a wide range of concentrations.

Indication

Short-term relief of moderate to severe postoperative acute pain.

Treatment should only be started in hospitals. The maximum duration of treatment is 2 days.

Contraindication

Ketorolac is contraindicated:

patients who have previously experienced hypersensitivity reactions to ketorolac, any of the excipients or other NSAIDs and patients with a history of allergic reactions to aspirin or other prostaglandin synthesis inhibitors (severe anaphylactic reactions have been observed in such patients). Such reactions included asthma, rhinitis, angioedema or urticaria; patients with a history of bronchial asthma; children under 16 years of age; patients with active peptic ulcer, recent gastrointestinal bleeding, ulceration or perforation; as with other NSAIDs, patients with severe heart failure, hepatic failure and renal failure; patients with moderate or severe renal failure (serum creatinine level greater than 160 μmol/l) or patients at risk of developing renal failure due to volume depletion or dehydration; during pregnancy, labor and delivery, during breastfeeding; as a prophylactic analgesic before surgery due to inhibition of platelet aggregation and during surgery due to increased risk of bleeding; due to inhibition of platelet function in patients with suspected or confirmed cerebrovascular bleeding, patients with a high risk of bleeding or incomplete cessation of bleeding, as well as patients with a high risk of bleeding, such as hemorrhagic diatheses, including coagulation disorders; patients receiving anticoagulants, including warfarin and low doses of heparin (2500-5000 units every 12 hours); with simultaneous treatment with acetylsalicylic acid or other NSAIDs (including selective cyclooxygenase-2 inhibitors); for neuraxial (epidural or intrathecal) administration due to alcohol content; in combination with oxpentifylline; simultaneous treatment with probenecid or lithium salts; patients with complete or partial nasal polyps syndrome, angioedema or bronchospasm.

Interaction with other medicinal products and other types of interactions

Ketorolac is extensively bound to plasma proteins (average 99.2%) and its binding is concentration dependent.

Medicines that should not be taken simultaneously with ketorolac

Ketorolac should not be used with other acetylsalicylic acid preparations or with other NSAIDs, including selective cyclooxygenase-2 inhibitors, as this may increase the risk of induction of serious adverse events associated with the action of NSAIDs.

Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. In contrast to the prolonged effect after taking aspirin, platelet function returns to normal within 24–48 hours after ketorolac discontinuation.

Ketorolac is not recommended in combination with anticoagulants such as warfarin, as the combined use of NSAIDs and anticoagulants may cause an increase in the anticoagulant effect.

Although studies do not indicate a significant degree of interaction between ketorolac and warfarin or heparin, the concomitant use of ketorolac and therapeutic agents that affect hemostasis, including therapeutic doses of anticoagulants (warfarin), prophylactic low-dose heparin (2500–5000 units every 12 hours), and dextrans, may be associated with an increased risk of bleeding.

There is evidence that some prostaglandin synthesis inhibitors inhibit renal clearance of lithium, leading to increased plasma lithium concentrations. Elevated plasma lithium concentrations have been reported during ketorolac therapy.

Concomitant use of ketorolac and probenecid resulted in increased plasma levels and T½ of ketorolac. Therefore, concomitant use of ketorolac and probenecid is contraindicated.

NSAIDs should not be used within 8–12 days after taking mifepristone, as the effectiveness of mifepristone may be reduced.

With the simultaneous administration of ketorolac and oxpentifylline, there is an increased tendency to bleeding.

Medicines that should be taken with caution in combination with ketorolac

As with all NSAIDs, caution should be exercised when co-administered with corticosteroids due to increased risk of gastrointestinal bleeding.

The risk of gastrointestinal bleeding increases with the concomitant use of NSAIDs with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs).

Some prostaglandin synthesis inhibitors have been reported to reduce the renal clearance of methotrexate and thus increase its toxicity.

Ketorolac trometamol does not alter the binding of digoxin to plasma proteins. In vitro studies indicate that at therapeutic concentrations of salicylates (300 μg/mL), ketorolac binding was reduced from approximately 99.2% to 97.5%, demonstrating a potential two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the binding of ketorolac to plasma proteins.

In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%, therefore, special attention is required when prescribing ketorolac to patients with cardiac decompensation.

Concomitant use with diuretics may reduce the diuretic effect and increase the risk of nephrotoxicity of NSAIDs.

As with all NSAIDs, caution should be exercised when co-administering cyclosporine due to the increased risk of nephrotoxicity.

There is also a risk of nephrotoxicity if NSAIDs are used in combination with tacrolimus.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. When ACE inhibitors and/or angiotensin II receptor antagonists are used in combination with NSAIDs, the risk of acute renal failure, usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients). Therefore, such combinations should be prescribed with caution, especially in elderly patients. Appropriate titration and attention to monitoring of renal function should be carried out before initiating concomitant use of such drugs with periodic monitoring thereafter.

NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly with the latter.

When ketorolac is used to relieve postoperative pain, the need for concomitant use of opioid analgesics is reduced.

Experimental evidence suggests that NSAIDs may increase the risk of quinolone-associated seizures. Patients taking NSAIDs and quinolones may be at increased risk of seizures.

There is no evidence in animal or human studies that ketorolac trometamol induces or inhibits hepatic enzymes involved in the metabolism of ketorolac itself or other drugs. Therefore, it is unlikely that ketorolac would alter the pharmacokinetics of other drugs as a result of enzyme induction or inhibition mechanisms.

Application features

Epidemiological data suggest that ketorolac may be associated with a higher risk of serious gastrointestinal toxicity compared with some other NSAIDs, especially when used off-label and/or for prolonged periods.

Doctors should be aware that some patients experience pain relief only 30 minutes after intravenous or intramuscular administration.

Concomitant use of ketorolac with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.

Undesirable effects can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms.

Ulcers, bleeding and perforation of the gastrointestinal tract

Gastrointestinal bleeding, ulceration or perforation, in some cases fatal, has been reported with all NSAIDs, with or without warning symptoms or a history of serious gastrointestinal events.

In a non-randomized, post-marketing observational inpatient study, increased rates of clinically serious gastrointestinal bleeding were observed in patients < 65 years of age receiving a mean daily dose of > 90 mg of intramuscular ketorolac compared to patients receiving parenteral opioids.

Elderly people have an increased incidence of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, in some cases with fatal outcome.

The risk of gastrointestinal bleeding, ulceration or perforation increases with higher doses of NSAIDs, including intravenous ketorolac. The risk is also increased in patients with a history of ulceration, especially complicated by bleeding or perforation, and in the elderly. The risk of clinically significant gastrointestinal bleeding is dose-dependent. These patients should be started on the lowest possible dose. In such cases, as well as in cases of low-dose aspirin or other drugs with an increased risk of gastrointestinal adverse effects, additional gastroprotective agents, such as misoprostol or proton pump inhibitors, may be considered. The age-related risk of gastrointestinal bleeding and perforation is common to all NSAIDs. Compared with young people, elderly patients have a longer plasma half-life and reduced plasma clearance of ketorolac. A longer dosing interval is recommended.

NSAIDs should be prescribed with caution to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated. Patients with a history of gastrointestinal disease, especially the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly during the initial stages of treatment. If a patient receiving intravenous ketorolac develops gastrointestinal bleeding or ulceration, treatment should be discontinued.

Particular caution should be exercised in patients who are taking concomitant medications that may increase the risk of ulceration or bleeding: for example, when using oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (e.g., aspirin).

Concomitant use with anticoagulants (such as warfarin) is contraindicated.

As with other NSAIDs, the frequency and severity of gastrointestinal complications may increase with increasing dose and duration of treatment with intravenous ketorolac. The risk of clinically serious gastrointestinal bleeding is dose-dependent. This is especially true in elderly patients receiving an average daily dose of intravenous ketorolac greater than 60 mg/day. A history of peptic ulcer disease increases the likelihood of developing serious gastrointestinal complications during therapy with ketorolac.

Effect on hemostasis

Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time was increased but did not exceed the normal range of 2–11 minutes. In contrast to the prolonged effect after aspirin, platelet function returned to normal within 24–48 hours after ketorolac discontinuation.

In the post-marketing period, reports of bleeding from postoperative wounds associated with urgent parenteral administration of ketorolac intravenously or intramuscularly during surgery have been received. Therefore, ketorolac should not be prescribed to patients undergoing surgery with a high risk of bleeding or in whom bleeding has not been completely stopped. Caution should be exercised in cases where stable hemostasis is important, for example, in cosmetic or outpatient surgeries, prostatectomy or tonsillectomy. Hematomas and other signs of bleeding from wounds, as well as nosebleeds, have been observed with ketorolac. When prescribing ketorolac, its similarity to other NSAIDs that inhibit cyclooxygenase and the potential risk of bleeding, especially in elderly patients, should be taken into account.

Skin reactions

Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely with the use of NSAIDs. The risk of these reactions is highest at the beginning of treatment, with the first manifestations occurring in most cases within the first month of treatment. Ambit® should be discontinued at the first appearance of skin rash, mucosal lesions or other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

Patients with SLE and mixed connective tissue disease may be at increased risk of developing aseptic meningitis.

Sodium/fluid retention in cardiovascular disease and peripheral edema

Caution should be exercised in patients with a history of hypertension and/or heart failure, as fluid retention and edema have been reported in association with the use of NSAIDs.

Fluid retention, hypertension, and edema have been reported in some patients taking NSAIDs, including ketorolac; therefore, ketorolac should be used with caution in patients with cardiac decompensation, hypertension, or similar conditions.

Effects on the cardiovascular system and cerebral circulation

Patients with hypertension and/or a history of mild to moderate congestive heart failure should be closely monitored as fluid retention and edema have been reported with NSAID therapy.

Clinical and epidemiological studies suggest that the use of coxibs and some NSAIDs (especially at high doses) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although no increase in the incidence of thrombotic events such as myocardial infarction has been observed with ketorolac, there are insufficient data to exclude such a risk with ketorolac.

Ketorolac should be prescribed to patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease only after careful consideration of the benefits and risks of such treatment. Ketorolac should also be used with caution in patients at risk for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smokers).

Patients with impaired cardiovascular system, renal and hepatic function

Caution should be exercised in patients with pathologies that may lead to a decrease in blood volume and/or renal blood flow, where renal prostaglandins play a compensatory role in maintaining renal perfusion. In such cases, the use of non-steroidal anti-inflammatory drugs (NSAIDs) may cause a dose-dependent decrease in prostaglandin production and provoke overt renal failure. The risk of such a reaction is highest in patients with impaired water balance due to blood loss or severe dehydration, in patients with impaired renal and hepatic function, heart failure, in the elderly and in patients taking diuretics. In this group, renal function should be monitored. Usually, after discontinuation of NSAID treatment, the patient's condition returns to that which was before the start of treatment. Impaired recovery of fluid/blood loss during surgery, which causes hypovolemia, may cause renal dysfunction, which in turn may be aggravated by the use of ketorolac. The decrease in interstitial fluid volume should be corrected; careful monitoring of serum urea and creatinine levels and monitoring of urine output is necessary until blood volume is normal. In patients undergoing renal dialysis, ketorolac clearance is approximately half that of normal and the terminal half-life is increased approximately 3-fold.

As with other NSAIDs, ketorolac should be used with caution in patients with impaired renal function or a history of renal disease because it is a potent inhibitor of prostaglandin synthesis. Caution should be exercised because nephrotoxicity has been observed with ketorolac and other NSAIDs in patients with pathologies that could lead to a decrease in blood volume and/or renal blood flow, where renal prostaglandins play a compensatory role in maintaining renal perfusion.

In such cases, the use of ketorolac or other NSAIDs may cause a dose-dependent decrease in prostaglandin production and provoke overt renal failure. The risk group includes patients with impaired renal function, hypovolemia, heart failure, impaired liver function, patients taking diuretics, and elderly patients. Usually, after discontinuation of treatment with ketorolac or other NSAIDs, the patient's condition returns to what it was before the start of treatment.

As with other prostaglandin synthesis inhibitors, increases in serum urea, creatinine, and potassium have been reported with ketorolac trometamol, which may occur after a single dose.

Use in patients with renal impairment: Since ketorolac trometamol and its metabolites are excreted primarily by the kidneys, ketorolac should not be administered to patients with moderate to severe renal impairment (serum creatinine >160 μmol/L). Patients with mild renal impairment should be given lower doses (not more than 60 mg/day intramuscularly or intravenously) and renal function should be monitored periodically.

Use in patients with liver disease: In patients with impaired liver function due to cirrhosis, ketorolac clearance and terminal half-life are not clinically significantly altered.

One or more liver function tests may be elevated. These abnormalities may be transient, persistent, or progress with continued treatment. In controlled clinical trials, elevations of ALT or AST (greater than three times the upper limit of normal) occurred in less than 1% of patients. If clinical symptoms suggestive of liver dysfunction or apparent systemic manifestations occur, ketorolac should be discontinued.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (such as anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) may occur in patients with a history of hypersensitivity to aspirin, other NSAIDs, or intravenous ketorolac, as well as in those who have not previously experienced hypersensitivity reactions. These reactions are possible in individuals with angioedema, a history of bronchospastic reactions (e.g., asthma), or nasal polyps. Anaphylactoid reactions such as anaphylaxis may be fatal. Therefore, ketorolac should not be used in patients with a history of asthma, complete or partial nasal polyposis, edema, or bronchospasm.

Fertility-related precautions

As with other cyclooxygenase/prostaglandin synthesis inhibitors, ketorolac may impair fertility; it is not recommended in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation for infertility should discontinue ketorolac.

Fluid retention and swelling

Fluid retention, hypertension, and edema have been reported in some patients taking ketorolac; therefore, ketorolac should be used with caution in patients with cardiac decompensation, hypertension, or similar conditions.

Caution is recommended when administering methotrexate concomitantly with drugs that inhibit prostaglandin synthesis, as they reduce the renal clearance of methotrexate and thus increase its toxicity.

Drug abuse and dependence

Ketorolac is not addictive. No withdrawal symptoms have been observed following abrupt discontinuation of intravenous ketorolac.

This product contains 10 vol. % ethanol (alcohol), i.e. 100 mg/ml, equivalent to 3 ml beer, 1.25 ml wine per dose. Harmful for patients with alcoholism. Caution should be exercised when used in pregnant and breastfeeding women, children, and patients with liver disease and epilepsy.

1 ml of ketorolac trometamol solution for injection contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially sodium-free.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some patients may experience dizziness, drowsiness, fatigue, visual disturbances, headache, vertigo, insomnia, or depression after using ketorolac. If such disorders are observed, patients should not drive or operate machinery.

Use during pregnancy or breastfeeding

The safety of ketorolac in pregnant women has not been established. Studies in rats and rabbits at maternally toxic doses of the drug have not revealed any teratogenic effects. In rats, prolonged gestation and/or delayed parturition have been observed. Congenital anomalies have been reported with NSAIDs in humans, but their incidence is low and no discernible trend is observed.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-foetal development. Epidemiological data indicate an increased risk of miscarriage, cardiac malformations and gastroschisis after the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to about 1.5%. The risk is believed to increase with increasing dose and duration of treatment. In animal studies, the use of prostaglandin synthesis inhibitors has resulted in pre- and post-implantation losses and embryo-foetal death. In addition, an increased number of congenital malformations, including cardiovascular diseases, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

During pregnancy, all prostaglandin synthesis inhibitors may contribute to the development of the following disorders in the fetus:

cardiopulmonary toxicity (premature closure of the patent ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligohydramnios;

At the end of pregnancy, the mother and newborn:

possibility of increased bleeding time, as antiplatelet effect may be observed even at low doses; inhibition of uterine contractile activity, which may lead to delayed or prolonged labor.

Approximately 10% of ketorolac crosses the placenta.

Labor and delivery

The use of ketorolac is contraindicated during labor and delivery because, as a result of its inhibitory effect on prostaglandin synthesis, it may negatively affect fetal hematopoiesis and suppress uterine contractions, thereby increasing the risk of bleeding.

There is an increased likelihood of bleeding in both the mother and the baby.

Breast-feeding

Ketorolac and its metabolites have been shown to pass into the fetus and milk in animals. Ketorolac has been detected in human breast milk at low concentrations and is therefore contraindicated in nursing mothers.

Method of administration and doses

Ketorolac is intended for intramuscular or bolus intravenous injection. Bolus intravenous doses should be administered over at least 15 seconds. Ketorolac should not be used for epidural or spinal administration.

The onset of analgesic effect after injection is similar and is about 30 minutes with its maximum intensity within 1–2 hours. The average duration of analgesia is 4–6 hours.

Dose selection and adjustment should be made according to the intensity of pain and the corresponding response to the administration of the drug.

Continuous intramuscular administration of multiple daily doses of ketorolac should not exceed 2 days, as the risk of adverse reactions increases with prolonged use. Experience with long-term use is limited, as the vast majority of patients were transferred to oral administration or after a period of intramuscular administration, patients no longer required analgesic therapy.

The likelihood of side effects can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms.

Adults

The recommended initial dose of ketorolac is 10 mg, followed by 10-30 mg every 4-6 hours (if necessary). In the initial postoperative period, ketorolac can be administered every 2 hours if necessary. The minimum effective dose should be prescribed. The total daily dose should not exceed 90 mg for young patients, 60 mg for elderly patients, patients with renal insufficiency and patients weighing less than 50 kg. The maximum duration of treatment should not exceed 2 days.

The dose should be reduced in patients weighing less than 50 kg.

Concomitant use of opioid analgesics (morphine, pethidine) is possible for optimal analgesic effect in the early postoperative period, when pain is most acute. Ketorolac does not negatively affect opioid receptor binding and does not enhance the respiratory depression or sedative effects of opioid drugs. When used in combination with intramuscular/intravenous administration of ketorolac, the daily opioid dose is usually lower than usual. However, the side effects of opioids should still be considered, especially in surgical intervention.

Elderly patients

Elderly patients are at increased risk of serious adverse reactions. If NSAIDs are considered necessary, the lowest effective dose should be used for the shortest duration. Patients should be monitored regularly for gastrointestinal bleeding during NSAID therapy. The total daily dose should not exceed 60 mg.

The drug is contraindicated in moderate and severe renal impairment. In less severe impairment, the dosage should be reduced (not higher than 60 mg/day intravenously or intramuscularly).

Children

Safety and efficacy in children have not been established. Therefore, ketorolac is not recommended for use in children under 16 years of age.

Overdose

Symptoms

Single overdoses of ketorolac at various times have resulted in abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction, which resolved after drug withdrawal.

Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression, and coma may occur after taking NSAIDs, although these symptoms are rare.

In addition, headache, epigastric pain, disorientation, agitation, drowsiness, dizziness, tinnitus and fainting are possible, as well as rare cases of diarrhea or isolated convulsions.

Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur with overdose.

Treatment

Patients should receive symptomatic and supportive treatment following NSAID overdose. There is no specific antidote. Dialysis does not significantly remove ketorolac from the blood due to its high protein binding.

If an overdose that can cause toxicity is detected within the first hour, activated charcoal or gastric lavage can be used as a life-threatening therapy for adult patients.

In addition, adequate diuresis should be ensured. Liver and renal function should also be monitored and the patient should be observed for at least 4 hours after ingestion of a dose likely to cause toxicity. Diazepam should be used in the event of repeated or prolonged seizures. Other therapeutic measures may also be considered depending on the clinical condition of the patient.

Adverse reactions

Post-marketing period

The following undesirable effects may occur in patients receiving intravenous ketorolac; the frequency is unknown because these were reported voluntarily from a population of uncertain size.

Gastrointestinal: The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcer, ulceration, perforation or gastrointestinal bleeding may occur, sometimes fatal, especially in the elderly. Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain/discomfort, melena, haematemesis, stomatitis, ulcerative stomatitis, eructation, flatulence, esophagitis, gastrointestinal ulcer, rectal bleeding, pancreatitis, dry mouth, feeling of fullness in the stomach, exacerbation of ulcerative colitis and Crohn's disease have been reported. Gastritis has been observed less frequently.

Infections: Aseptic meningitis (especially in patients with pre-existing autoimmune disorders such as SLE, mixed connective tissue disease), with symptoms such as neck stiffness, headache, nausea, vomiting, fever or disorientation.

Blood and lymphatic system disorders: Thrombocytopenia. In addition, purpura, neutropenia, agranulocytosis, aplastic anemia and hemolytic anemia have been observed.

Immune system disorders: Anaphylaxis, anaphylactoid reactions, anaphylaxis-like reactions, anaphylactoid reactions which may be fatal; hypersensitivity reactions such as bronchospasm, flushing, rash, hypotension, laryngeal oedema.

Such reactions are possible in individuals with a history of angioedema or bronchospastic reactions (e.g., asthma or nasal polyps).

Metabolic and nutritional disorders: Anorexia, hyperkalemia, hyponatremia.

Mental disorders. P