Paracetamol/ Caffeine/ Codeine/ Diphenhydramine

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

Caffeine
Contraindications 

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

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Anxiety 
• Neonates 
• Cardiovascular disease
• History of peptic ulcer
• Gastroesophageal reflux
• History of seizure disorder
• Concomitant use with transcutaneous electrical nerve stimulation 

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
• Coadministration with 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

Diphenhydramine
Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Asthma
• Narrow-angle glaucoma
• Prostatic hypertrophy
• Stenosing peptic ulcer
• Pyloroduodenal obstruction
• Bladder neck obstruction
• Porphyria

Cautions

• Breastfeeding
• Moderate to severe renal impairment
• Hepatic impairment 
• Elderly
• Glaucoma
• Urinary retention
• Myaesthenia gravis
• Epilepsy
• Bronchitis
• Chronic obstructive pulmonary disease
• Tinnitus
• Prolonged use

Additional contraindications for this combination product

• Coadministation with monoamine oxidase inhibitors  

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

Pain
-Muscle and joint stiffness
-Neuralgia
-Dysmenorrhoea/premenstrual tension
-Headache/tension headaches
-Lower back pain
-Joint pain
-Toothache
-Dental pain 

Paracetamol/ Caffeine/ Codeine/ Diphenhydramine
400/50/10/5 (mg)

• Oral (tab): 1-2 tab, 4hrly; Max: 8 tab/24hrs

Not established for use in children below 12 years

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

Pregnancy

• FDA Pregnancy Category C (Paracetamol, Caffeine, Codeine) 

Breastfeeding

• Contraindicated (Codeine) 

Renal Impairment

• Caution; dose adjustment recommended (Codeine) 

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
• Severe: Contraindicated (Codeine) 

Elderly

• Caution; dose adjustment recommended (Codeine) 

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warning

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

Caffeine
Central Nervous System Disorders

• Agitation
• Delirium
• Dizziness
• Hallucination
• Headache
• Insomnia
• Irritability
• Psychosis
• Restlessness

Gastrointestinal Disorders

• Oesophageal motility disorder (sphincter tone decreased)
• Gastritis

Genitourinary Disorders

• Diuresis

Musculoskeletal Disorders

• Fasciculations

Skin and Subcutaneous Tissue Disorders

• Urticaria

Sensory Disorders

• Increased intraocular pressure
• Miosis

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

Diphenhydrmine
Central Nervous System Disorders

• Sedation
• Disturbances in attention
• Unsteadiness
• Dizziness
• Seizures
• Headache
• Paraesthesia
• Dyskinesias
• Fatigue
• Confusion
• Paradoxical excitement

Cardiovascular Disorders

• Tachycardia
• Palpitations

Respiratory Disorders

• Dyspnoea
• Thickening of bronchial secretions

Gastrointestinal Disorders

• Dry mouth
• Nausea and vomiting

Genitourinary Disorders

• Urinary difficulty
• Urinary retention

Musculoskeletal Disorders

• Muscle twitching

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Urticaria
• Angioedema

Sensory Disorders

• Blurred vision
• Tinnitus

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

Paracetamol

• Metoclopramide 
• Domperidone
• Colestyramine
• Oral anticoagulants
• Chloramphenicol

Caffeine

• Adenosine
• Cocaine
• CYP1A2 Inhibitors 
• Linezolid 

Codeine

• Alcohol
• Anaesthetics
• Anti-arrhythmic agents
• Central nervous system depressants
• Antihistamines
• Domperidone 
• Metoclopramide
• Cimetidine

Diphenhydramine

• Central nervous system depressants
• Monoamine oxidase inhibitors
• Anticholinergic agents
• CYP2D6 substrates

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.

Caffeine
Caffeine is a nonspecific adenosine receptor antagonist and acts as a central nervous system stimulant.

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. 

Diphenhydramine
Diphenhydramine is a histamine H1 antagonist that competes with free histamine for binding at histamine receptors. In addition to its usual anti-allergy actions, it also has significant sedative and antimuscarinic properties.

COMBINATION PREPARATIONS

Paracetamol/ Caffeine/ Codeine/ Diphenhydramine

Tablet 400mg/50mg/10mg/5mg

• Lenadol (Pharmacare)
• Propain (Adcock)
• Tensolve (Pharmacare)