Paracetamol/ Meprobamate/ Codeine

Registered South African indications:

• Pain

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Paracetamol
Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Severe hepatic impairment

Cautions

• Pregnancy
• Renal impairment
• Mild to moderate hepatic impairment

Meprobamate
Contraindications 

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Pregnancy
• Substance abuse
• Acute intermittent porphyria
• Acute pulmonary insufficiency
• Respiratory depression

Cautions 

• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Depression
• Suicidal ideation or intent
• Respiratory disease
• Muscle weakness
• Epilepsy
• High dosages
• Prolonged use
• Abrupt withdrawal
• May impair ability to drive and operate machinery

Codeine
Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Breastfeeding
• Severe hepatic impairment
• Acute respiratory depression
• Obstructive airways disease
• Acute alcoholism
• Raised intracranial pressure or head injury
• Comatose patients
• Conditions where inhibition of peristalsis is to be avoided
• CYP2D6 ultra-rapid metabolisers

Cautions

• Pregnancy
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly patients
• Debilitated patients
• Asthma and decreased respiratory reserve
• Misuse, abuse potential or dependence
• Dependency and addiction with prolonged and continuous use
• Hypotension
• Hypothyroidism
• Prostatic hypertrophy
• Urethral stricture
• Adrenocortical insufficiency
• Inflammatory or obstructive bowel disorders
• Shock
• Convulsive disorders
• Myasthenia gravis
• Children with compromised respiratory function
• Biliary tract disorders
• May impair ability to drive and operate machinery

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

Relief of pain - mild to moderate
Relief of pain associated with tension

Paracetamol/ Meprobamate/ Codeine
400/200/8 (mg)

• Oral (cap): 1-2 cap, 6-8hrly; Max: 8 cap/24hrs

320/150/8 (mg)

• Oral (cap): 2 cap, 6-8hrly

Not established for use in children younger than 12 years 

Recommendations for this combination product as per highest risk category when comparing individual active ingredients

Pregnancy

• Caution (Meprobamate, Codeine)
• There is no evidence as to drug safety in human pregnancy, nor is there evidence that it is free from hazard. Meprobamate diffuses across the placenta, and should not be used during pregnancy, especially during the first three months, unless there are compelling reasons, and the benefit to the mother is considered to outweigh any potential risks to the developing foetus
• Not recommended during pregnancy due to neonatal withdrawal symptoms and impaired effect of the foetus. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. During labour opioids enter the foetal circulation and may cause respiratory depression in the neonates. Respiratory malformation in neonates may be associated with exposure to codeine during pregnancy. Gastric stasis and a risk of inhalation pneumonia could occur in the mother during labour. Administration should be avoided during the late stages of labour and during the delivery of a premature infant
• Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage. A large amount of data on pregnant women indicate neither malformative nor feto/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency

Breastfeeding

• Contraindicated (Codeine)
• Codeine is contraindicated in women during breastfeeding. At normal therapeutic doses, codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breastfed infant
• However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal
• Meprobamate appears in breast milk at concentrations up to four times those in maternal plasma and may cause drowsiness in the infant. Meprobamate should not be used by patients who are breastfeeding
• Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breastfeeding

Renal Impairment

• Caution; dose adjustment recommended (Paracetamol, Meprobamate, Codeine)

Paracetamol

CrCl (ml/min)	Maximum Dose
≥ 50	No adjustment necessary
10-50	500mg, 6hrly
< 10	500mg, 8hrly

Meprobamate

CrCl (ml/min)	Dose frequency
10-50	Administer, 9-12hrly
<10	Administer, 12-18hrly
Hemodialysis	No adjustment necessary
Peritoneal dialysis	Administer, 12-18hrly
Continuous renal replacement therapy (CRRT)	Administer, 9-12hrly

Codeine

GFR (ml/min)	Dose
> 50	No adjustment necessary
10-50	Administer 75% of the recommended dose
< 10	Administer 50% of the recommended dose
Haemodialysis	No data

Note: Recommendations based on individual agents

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended (Paracetamol, Codeine)
• Paracetamol: Max: 2g/24hrs
• Codeine: Lower initial doses or longer dosing intervals followed by careful titration are recommended
• Severe: Contraindicated (Paracetamol, Codeine)

Elderly

• Caution; dose adjustment recommended (Meprobamate, Codeine)
• Meprobamate: Reduce dose by ≥ 50%
• Codeine: Lower initial doses or longer dosing intervals followed by careful titration are recommended

Porphyria Information

• Not yet classified (NC) (Meprobamate)

Drugs in Sport

• Permitted - No warnings

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Paracetamol
Respiratory Disorders

• Bronchospasm

Hepatobiliary Disorders

• Hepatic dysfunction

Immune, Blood and Lymphatic System Disorders

• Anaphylaxis
• Cutaneous hypersensitivity reactions 
• Angiodema
• Stevens Johnson syndrome
• Thrombocytopenia 
• Agranulocytosis
• Methaemoglobinaemia

Meprobamate
Central Nervous System Disorders

• Drowsiness
• Dizziness 
• Ataxia
• Paraesthesia
• Paradoxical excitement

Cardiovascular Disorders

• Hypotension

Gastrointestinal Disorders

• Nausea and vomiting
• Stomatitis
• Proctitis

Skin and Subcutaneous Tissue Disorders

• Skin rashes
• Urticaria
• Itchy maculopapular rashes
• Erythema
• Erythema multiforme
• Exfoliative dermatitis 
• Stevens Johnson syndrome
• Bullous dermatitis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions 
• Non-thrombocytopenic purpura
• Thrombocytopenia
• Agranulocytosis
• Aplastic anaemia
• Pancytopenia 

Codeine
Central Nervous System Disorders

• Dizziness
• Drowsiness
• Mood changes
• Euphoria 
• Dysphoria
• Mental depression
• Restlessness
• Confusion
• Headache
• Raised intracranial pressure
• Hallucinations
• Nightmares
• Vertigo

Cardiovascular Disorders

• Tachycardia
• Palpitations
• Bradycardia 
• Postural hypotension
• Facial flushing 
• Hypotension

Respiratory Disorders

• Dyspnoea
• Respiratory depression

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Dry mouth
• Stomach cramps
• Pancreatitis
• Biliary spasm

Genitourinary System Disorders

• Sexual dysfunction
• Erectile dysfunction
• Decreased potency
• Decreased libido
• Difficulty with micturation
• Urinary retention
• Ureteric spasm
• Dysuria

Endocrine and Metabolic Disorders

• Hyperglycaemia
• Anorexia

Musculoskeletal Disorders

• Uncontrolled muscle movements
• Muscle rigidity 

Skin and Subcutaneous Tissue Disorders 

• Skin rashes
• Urticaria
• Pruritus
• Sweating 
• Facial oedema

Immune System Disorders

• Maculopapular rash
• Fever
• Splenomegaly 
• Lymphadenopathy 

Sensory Disorders

• Blurred or double vision or other changes in vision
• Miosis

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Paracetamol

• Metoclopramide 
• Domperidone
• Colestyramine
• Oral anticoagulants
• Chloramphenicol

Meprobamate

• Warfarin
• Systemic steroids
• Phenytoin
• Griseofulvin
• Rifampicin
• Phenothiazines 
• Tricyclic antidepressants
• Central nervous system depressants

Codeine

• Alcohol
• Anaesthetics
• Antiarrhythmic agents
• Central nervous system depressants
• Antihistamines
• Domperidone 
• Metoclopramide
• Cimetidine

None routine 

Paracetamol
Paracetamol increases the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin synthesis. It does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects.

Meprobamate
Meprobamate is a carbamate with hypnotic, sedative and some muscle relaxant properties.  It binds to gamma-amino butyric acid receptors in the central nervous system, including the thalamus and limbic system.

Codeine
Codeine is a centrally acting weak analgesic. It exerts its effect through mu opioid receptors. It resembles morphine in its pharmacodynamic actions although much weaker in its effects. 

COMBINATION PREPARATIONS

Paracetamol/ Meprobamate/ Codeine

Capsule 320mg/150mg/8mg

• Stilpane (Pharmacare)

Capsule 400mg/200mg/8mg

• Synaleve (Adcock)
• Trinagesic (Adcock)