Metamizole Sodium/ Hyoscine Butylbromide

Registered South African indications:

• Biliary and renal colic, associated with abdominal pain, acute spastic pain, spastic functional dysmenorrhoea, and painful spastic conditions of the female genital system

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Hypersensitivity to pyrazolone or pyrazolidines (e.g. metamizole, isopropylaminophenazone, propyphenazone, phenazone or phenylbutazone) including patients who developed agranulocytosis, for example, following use of one of these substances
• Third trimester of pregnancy
• Granulocytopenia
• Patients in whom aspirin or other nonsteroidal anti-inflammatory drugs induce symptoms of asthma, rhinitis or urticaria
• Known analgesic-induced asthma syndrome or known analgesic intolerance of the urticaria-angioedema type, i.e. patients who develop bronchospasm or other anaphylactoid reactions in response to salicylates, paracetamol or other non-narcotic analgesics such as diclofenac, ibuprofen, indomethacin or naproxen
• Impaired bone marrow function (e.g., after treatment with cytostatic agents) or diseases of the haemopoietic system
• Genetic glucose-6-phosphate-dehydrogenase deficiency (risk of haemolysis)
• Acute intermittent hepatic porphyria (risk of triggering a porphyria attack)
• Pronounced tachycardia, hypotension, anaphylaxis and cardiac diseases or history of cardiac disease or hypertension
• Megacolon
• Myasthenia gravis
• Asthma
• Rare hereditary conditions that may be incompatible with an excipient of the product
• Closed angle glaucoma or patients with a narrow angle between the iris and the cornea since its use may lead to increased intra-ocular pressure
• Prostatic enlargement, patients suffering from paralytic ileus or pyloric stenosis where its use may lead to obstruction
• Patients where the ambient temperature is high (especially children)

South African recommendations

• First and second trimester of pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Unexplained abdominal pain

• Persistent or worsening abdominal pain accompanied by symptoms such as fever, nausea, vomiting, altered bowel habits, abdominal tenderness, decreased blood pressure, fainting, or presence of blood in stool. Diagnostic measures required

Haematologic reactions

• Risk of agranulocytosis with metamizole sodium; prolonged use not advised. If symptoms like general malaise, infection, fever, bruising, bleeding, or pallor occur, or if there are signs of hematologic reactions like agranulocytosis, aplastic anaemia, thrombocytopenia, or pancytopenia, treatment should be stopped and blood count monitored until normal. Immediate discontinuation required upon signs of blood dyscrasia (e.g. general malaise, infection,
  persistent fever, bruising, bleeding or pallor)

Anaphylactic/anaphylactoid reactions

• Higher risk of severe anaphylactoid reactions to metamizole sodium/ hyoscine butylbromide in patients with:
  • Analgesic-induced asthma syndrome or urticaria-angioedema type analgesic intolerance
  • Bronchial asthma with rhinosinusitis and nasal polyps
  • Chronic urticaria
  • Alcohol intolerance, indicated by reactions to small amounts of alcohol
  • Susceptibility to shock from metamizole
  • Patients with asthma or atopy are at a heightened risk for anaphylactic shock
  • Patients who reacted to metamizole sodium/ hyoscine butylbromide may also react similarly to other pyrazolones, pyrazolidines, and non-narcotic analgesics

Severe skin reaction

• Life-threatening reactions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can occur with metamizole use. If symptoms like skin rash, blisters, or mucosal injury appear, treatment with metamizole sodium/ hyoscine butylbromide must stop immediately and never be restarted. Patients should be informed about these reactions to seek medical advice if symptoms develop. Monitoring is crucial, especially during the initial weeks of treatment

Gastrointestinal bleeding

• Gastrointestinal bleeding has been reported with metamizole use. This risk may be higher if patients also take other treatments like NSAIDs or overdose on metamizole

Intraocular pressure

• Anticholinergic agents like hyoscine butylbromide can raise intraocular pressure, potentially harming those with undetected narrow angle glaucoma. Patients experiencing a painful, red eye with vision loss should urgently consult an ophthalmologist

Drug-induced liver injury

• Acute hepatitis has been reported in patients using metamizole, occurring days to months after starting treatment. Symptoms include elevated liver enzymes, possibly with jaundice, often alongside other hypersensitivity reactions or signs of autoimmune hepatitis. While most recover after stopping metamizole, some cases progress to acute liver failure requiring liver transplantation. An immuno-allergic mechanism may be involved
• Patients should seek medical attention for liver injury symptoms, discontinue metamizole, and undergo liver function testing. Metamizole shouldn't be restarted if it's suspected to have caused liver injury previously

Risk in specific populations

• Exercise caution when using in elderly men and patients with fever. Metamizole sodium/hyoscine butylbromide should be used judiciously in the elderly or those with compromised renal or hepatic function. In diabetics, the pyrazolone derivative might interfere with certain blood sugar tests using the glucose-oxidase method (GOD)

Contains sucrose

• Metamizole sodium/hyoscine butylbromide has sucrose, which might impact diabetic patients' blood sugar levels. It's not advised to take metamizole sodium/hyoscine butylbromide for those with rare hereditary conditions like fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency

May impair ability to drive and operate machinery

• Metamizole sodium/hyoscine butylbromide can moderately impact driving and machine operation. It may cause drowsiness, vision disturbances, and reduced mental alertness. Patients should avoid driving, operating machinery, or conducting hazardous tasks, especially when combined with alcohol. Even at recommended doses, precautions should be taken

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Biliary and renal colic, associated with abdominal pain, acute spastic pain, spastic functional dysmenorrhoea, and painful spastic conditions of the female genital system

Metamizole Sodium/ Hyoscine Butylbromide

250/10 (mg)

• Oral (tab): 1-2 tab, three times a day until pain is relieved

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Third trimester: Contraindicated
• First and second trimester: Caution; not recommended
• Safety during pregnancy has not been established. Metamizole sodium monohydrate passes the placental barrier and should therefore only be used during pregnancy after careful consideration of the indications

Breastfeeding

South African recommendations

• Caution; not recommended
• Safety during breastfeeding has not been established
• Metamizole sodium monohydrate is excreted in breastmilk and should therefore only be used during breastfeeding after careful consideration of the indications
• The breakdown products of metamizole sodium monohydrate are excreted into breastmilk in considerable amounts and a risk to the breastfed infant cannot be excluded. Especially the repeated use during breastfeeding must therefore be avoided. In case of a single administration of metamizole sodium monohydrate mothers are advised to collect and discard the breastmilk for 48 hours from its administration

Fertility

South African recommendations

• No data on male and female fertility is available

South African recommendations

• Caution; no dose adjustment recommended
  Should only be used after consideration of the benefit-risk ratio and appropriate precautions must be taken for this population

South African recommendations

• Caution; no dose adjustment recommended
  Should only be used after consideration of the benefit-risk ratio and appropriate precautions must be taken for this population

South African recommendations

• Caution; no dose adjustment recommended
  Should only be used after consideration of the benefit-risk ratio and appropriate precautions must be taken for this population

Immune System Disorders

• Anaphylactic reaction (Less frequent)
• Anaphylactic shock including fatal outcome (Unknown)
• Dyspnoea (Unknown)
• Hypersensitivity (Unknown)
• Abnormal sweating (Unknown)
• Severe angioedema including the laryngeal region (Unknown)
• Severe bronchospasm (Unknown)
• Arrhythmia (Unknown)
• Decreased blood pressure with sometimes initially increased blood pressure (Unknown)

Eye Disorders

• Accommodation disorders (Less frequent)
• Dilatation of the pupils with loss of accommodation and photophobia (Unknown)
• Increased intra-ocular pressures (Unknown)

Cardiac Disorders

• Transient bradycardia followed by tachycardia (Unknown)
• Palpitations and dysrhythmia (Unknown)
• Kounis Syndrome (Unknown)

Vascular Disorders

• Hypotension (Frequent)
• Dizziness (Frequent)
• Shock (Less frequent)
• Flushing (Less frequent)

Gastrointestinal Disorders

• Dry mouth (Less frequent)
• Thirst (Unknown)
• Dryness of the mouth (Unknown)
• Difficulty in swallowing (Unknown)
• Reduction in the tone and motility of the gastrointestinal tract leading to constipation (Unknown)
• Gastrointestinal haemorrhage (Unknown)

Hepato-biliary Disorders

• Drug-induced liver injury (Unknown)
• Acute hepatitis (Unknown)
• Jaundice (Unknown)
• Increased liver enzymes (Unknown)
• Elevated serum hepatic enzymes with or without jaundice
• Autoimmune hepatitis
• Acute hepatic failure (requiring liver transplantation)

Skin and Subcutaneous Tissue Disorders

• Skin reactions (Less frequent)
• Maculo-papular rash (Less frequent)
• Toxic epidermal necrolysis (Less frequent)
• Stevens-Johnson syndrome (Less frequent)
• Flushing and dryness of the skin (Unknown)
• Milder reactions such as skin and mucosal reactions (Unknown)
  • Pruritus
  • Burning sensation
  • Erythema
  • Swelling
• More severe reactions such as generalised urticaria (Unknown)

Renal and Urinary Disorders

• Acute renal failure (Less frequent)
• Anuria (Less frequent)
• Interstitial nephritis (Less frequent)
• Oliguria (Less frequent)
• Proteinuria (Less frequent)
• Renal impairment (Less frequent)
• A desire to urinate with the inability to do so (urinary retention) (Unknown)
• Chromaturia (Unknown)
• Excretion of rubazonic acid, a harmless metabolite of metamizole, which may cause a red colouration of the urine (Unknown). This disappears upon discontinuation of treatment

Additional adverse reactions of individual components

Metamizole Sodium

Cardiovascular Disorders 

• Shock
• Systolic blood pressure values below 100mmHg in patients with unstable circulation
  • Myocardial infarction
  • Multiple injuries
  • Initial shock

Skin and Subcutaneous Tissue Disorders

• Allergic skin and mucosal reactions
• Very serious or even life-threatening bullous skin reactions, generally with mucous membrane involvement
  • Stevens-Johnson Syndrome
  • Lyell Syndrome

Immune, Blood and Lymphatic System Disorders

• Severe anaphylactic reaction
• Leucopoenia
• Agranulocytosis
  • High fever
  • Chills
  • Sore throat
  • Difficulty in swallowing, inflammation in the mouth, nose and throat as well as in the genital or anal region

Hyoscine-N-butylbromide
Central Nervous System Disorders

• Drowsiness
• Giddiness and staggering

Cardiovascular Disorders

• Transient bradycardia followed by tachycardia, with palpitations and arrhythmias

Gastrointestinal Disorders

• Dryness of the mouth with difficulty of swallowing and talking
• Thirst
• Reduction in the tone and mobility of the gastro-intestinal tract leading to constipation
• Vomiting

Genitourinary Disorders

• Urinary urgency, difficulty and retention 

Skin and Subcutaneous Tissue Disorders

• Flushing
• Dryness of the skin

Sensory Disorders

• Dilation of the pupils (mydriasis) with loss of accommodation (cycloplegia)
• Photophobia

Others

•  Retrosternal pain may occur due to increased gastric reflux

• Methotrexate
• Chlorpromazine
• Acetylsalicylic acid
• Bupropion
• Cyclosporin
• Anticholinergic agents
• Tricyclic antidepressants
• Antihistamines
• Quinidine
• Amantadine
• Disopyramide
• Tiotropium
• Ipratropium
• Atropine-like compounds
• Dopamine antagonists
• Metoclopramide
• Beta-adrenergic agents
• Oral anticoagulants
• Captopril
• Lithium
• Triamterene
• Diuretics
• Antihypertensives
• Digoxin
• Butyrophenones
• Phenothiazines

Other interactions

• Alcohol

None routine. Specific cases may require

• Full blood count
• Pulse rate
• Blood pressure

Additional observations

• Signs and symptoms of skin reactions
• Cyclosporin blood levels (if coadministered)
• Unexplained abdominal pain, with symptoms like fever, nausea, vomiting, changes in bowel movements, abdominal tenderness, decreased blood pressure, fainting or blood in stool

Risk of drug-induced liver injury associated with the use of metamizole-containing medicines

• Liver injury was observed to be predominantly of a hepatocellular pattern with an onset of a few days to months following treatment initiation with metamizole-containing medicines
• Signs and symptoms included elevated serum hepatic enzymes with or without jaundice, frequently in the context of other drug hypersensitivity reactions (e.g. skin rash, blood dyscrasias, fever and eosinophilia) or accompanied by features of autoimmune hepatitis
• There are cases reporting liver injury recurrence upon re-administration
• The mechanism of metamizole-induced liver injury is not clearly elucidated, but available data indicate an immuno-allergic mechanism
• In general, metamizole-containing medicines induced liver injury may progress to potentially serious outcomes, such as acute hepatic failure requiring liver transplantation

Advice to healthcare professionals 

• Early recognition of potential liver injury from the use of metamizole-containing medicines is essential
• Patients should be advised to look out for symptoms of potential liver injury and be encouraged to stop the use of metamizole-containing medicines and consult a healthcare professional if such symptoms arise. Symptoms may include right upper quadrant pain, persistent nausea and a complaint of yellow sclera
• Healthcare professionals are advised to assess and monitor liver function in patients presenting with signs and symptoms suggestive of any liver injury
• Re-exposure to metamizole-containing medicines is not recommended where no other cause of liver injury has been determined
• Healthcare professionals are urged to report any adverse reactions (ADRs) or product quality issues to SAHPRA via the eReporting link available on the SAHPRA website (www.sahpra.org.za). Alternatively, please complete the ADR reporting form from the Essential Medicines List (EML) Clinical Guide to report ADRs or product quality issues
• For more information on ADR reporting of metamizole-containing medicines listed below, please contact the SAHPRA vigilance unit at pvqueries@sahpra.org.za
• For full safety information, click here

Metamizole sodium monohydrate/ hyoscine-N-butylbromide is used to relieve spasm of the smooth muscle in the gastrointestinal tract, the biliary tract and the urogenital tract, where an analgesic as well as an antispasmodic effect is required.

COMBINATION PREPARATIONS

Metamizole Sodium/ Hyoscine butylbromide

Tablet 250mg/10mg

• Buscopan Co (Sanofi Aventis) originator
• Scopex Co (Adcock Ingram)