Metamizole Sodium/ Hyoscine Butylbromide

Registered South African indications:

• Acute colicky pains of the biliary, urinary and gastrointestinal tract - severe 

Contraindications

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Prior 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
• 3 months of pregnancy and 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)
• Glaucoma
• Hypertrophy of the prostate with urinary retention
• Mechanical stenosis in the gastrointestinal tract
• Paralytic or obstructive ileus
• Pronounced tachycardia
• Megacolon
• Myasthenia gravis
• Asthma
• Existing arterial hypotension and unstable circulatory state
• Patients being treated with anticoagulant drugs as intramuscular injection, since intramuscular haematoma may occur. In these patients, the intravenous route may be used
• Subcutaneous injection
• Intraarterial injection
• Rare hereditary conditions that may be incompatible with an excipient of the product
• Children <12 months. This medicinal product it is not recommended in children nor adolescents (under 18 years old), as safety and efficacy is not demonstrated in these patients
• Existing arterial hypotension and unstable circulatory state

Cautions

South African recommendations

• Pregnancy (where not contraindicated)
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Bronchial asthma, in particular in the presence of rhinosinusitis and nasal polyps
• Chronic urticaria
• Atopy
• Rapid IV injection
• Previous arterial hypotension
• Volume depletion or dehydration
• Unstable circulation or incipient circulatory failure (e.g. patients with heart attack or polytrauma)
• High fever
• Patients for whom a fall in blood pressure must be avoided at all costs, such as in severe coronary artery disease or relevant stenosis of the cerebral blood vessels
• Undiagnosed and untreated narrow-angle glaucoma
• Incorrect route of administration or improper injection technique
• History of cardiovascular disease risk factors
• Patients suffering from tachycardia
  - Thyrotoxicosis
  - Cardiac insufficiency or failure
  - In cardiac surgery
• History of cardiac disease or hypertension
• Patients suffering from existing disturbances of blood cell formation (e.g. under cytostatic treatment)
• Systolic blood pressure values <100mmHg in patients with unstable circulation
  - Myocardial infarction
  - Multiple injuries
  - Initial shock
• Alcohol intolerance
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Acute colicky pains of the biliary, urinary and gastrointestinal tract - severe

Metamizole Sodium/ Hyoscine Butylbromide

2500/20 (mg/5ml)

• IV/IM: 5ml, given as a slow injection over ≥5 minutes; Repeat 2-3 times a day if needed (at intervals of several hours)

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During administration, patient should ideally be in lying position

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DO NOT administer as subcutaneous or intraarterial injection. The administration of metamizole sodium/ hyoscine butylbromide injection should be under medical supervision and be monitored

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Should IV administration be impossible, the preparation may be given by IM injection

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See additional prescribing points: IM technique

Contraindicated

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Metamizole sodium/ hyoscine butylbromide is contraindicated in children under 12 months of age and is not recommended in children or adolescents (<18 years old), as safety and efficacy is not demonstrated

Pregnancy

South African recommendations

• When not contraindicated: Caution; not recommended
• 3 months of pregnancy and third trimester: Contraindicated
• Safety of hyoscine butylbromide 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 of hyoscine butylbromide 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 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 studies on the effects on human fertility have been conducted

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

Cardiovascular Disorders

• Arrhythmia
• Decreased blood pressure - with sometimes initially increased blood pressure
• Tachycardia
• Kounis Syndrome
• Shock
• Phlebitis

Respiratory Disorders

• Asthma in patients with analgesic asthma syndrome
• Dyspnoea
• Severe bronchospasm

Gastrointestinal Disorders

• Dry mouth
• Gastrointestinal haemorrhage

Hepatobiliary Disorders

• Hepatic injury (drug-induced liver injury (DILI))
• Elevated serum hepatic enzymes with or without jaundice
• Autoimmune hepatitis
• Acute hepatic failure (requiring liver transplantation)

Genitourinary Disorders

• Acute renal failure
• Anuria
• Interstitial nephritis
• Oliguria
• Proteinuria
• Renal impairment
• Urinary retention
• Chromaturia

Endocrine and Metabolic Disorders

• Hyperpyrexia
• Abnormal sweating

Skin and Subcutaneous Tissue Disorders

• Drug eruption
• Skin reactions
• Maculo-papular rash
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Skin and mucosal reactions
  - Pruritus
  - Burning sensation
  - Erythema
  - Swelling
• Generalised urticaria
• Injection site reaction (inj)
• Injection site pain (inj)
• Flushing
• Dry skin

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Leukopenia
• Agranulocytosis (including fatal cases)
  - Pyrexia
  - Chills
  - Oropharyngeal pain
  - Sore throat
  - Inflammation in the mucosa of the mouth, nose and throat
  - Dysphagia
  - Stomatitis
  - Rhinitis
  - Pharyngitis
  - Genital tract inflammation
  - Anal inflammation
• Increased red blood cell sedimentation rate
• Reduced or absent granulocytes
• Abnormal haemoglobin
• Abnormal red blood cell counts
• Abnormal platelet counts
• Anaphylactic reaction
• Anaphylactoid reaction (especially after parenteral administration)
• Anaphylactic shock, including fatal outcome
• Thrombocytopenia
• Sepsis (including fatal cases)
• Aplastic anaemia
• Pancytopenia (including fatal cases)
• Severe angioedema including the laryngeal region

Sensory Disorders

• Accommodation disorders
• Mydriasis
• Increased intraocular pressure

Additional adverse reactions of individual components

Metamizole Sodium

Cardiovascular Disorders 

• Shock

Skin and Subcutaneous Tissue Disorders

• Allergic skin and mucosal reactions
• Bullous skin reactions, generally with mucous membrane involvement
• Stevens-Johnson Syndrome
• Lyell Syndrome

Immune, Blood and Lymphatic System Disorders

• Severe anaphylactic reaction
• Leucopoenia
• Agranulocytosis

Hyoscine 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
• Constipation
• Vomiting

Genitourinary Disorders

• Urinary urgency

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

• Methotrexate
• Chlorpromazine
• Acetylsalicylic acid
• Bupropion
• Cyclosporin
• Anticholinergic agents
• Tri- and tetracyclic antidepressants
• Antihistamines
• Antipsychotics
• 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
• Interference with laboratory tests (See additional prescribing points)

None routine. Specific cases may require

• Full blood count
• Haemodynamic parameters
• Pulse rate
• Blood pressure

Additional observations

• Hypotensive reactions - in patients at risk of
• Signs and symptoms of skin reactions
• Cyclosporin blood levels (if coadministered)

IM administration technique

• Site of injection: Only in the upper, outer quadrant of the buttock
• Direction: Sagittally and directed towards the iliac crest
• Depth: A sufficiently long needle to ensure the injection reaches the muscle

Interference with laboratory tests

• In diabetic patients, the pyrazolone derivative can affect the enzymatic blood sugar assay by the glucose-oxidase method (GOD)

Incompatibilities

• Metamizole sodium/ hyoscine butylbromide injection should not be added to pH correcting intravenous solutions of high volume or parenteral nutrition (amino acids, lipids)
• Because of the possibility of incompatibilities, metamizole sodium/ hyoscine butylbromide injection must not be mixed with other agents in the same syringe

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/ hyoscine butylbromide has a selective antispasmodic action on the smooth muscle of the gastro-intestinal, biliary and genito-urinary tracts. It also has analgesic properties.

COMBINATION PREPARATIONS

Metamizole Sodium/ Hyoscine butylbromide

Injection (per 5ml) 2500mg/20mg

• Buscopan Co (Sanofi Aventis) originator