Paracetamol/ Caffeine/ Codeine/ Doxylamine

Registered South African indications:

• Pain
• Fever

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
• Severe 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
• Renal impairment
• Hepatic impairment
• Patients with anxiety
• Cardiovascular disease
• Symptomatic arrhythmias
• Peptic ulcers
• Gastro-oesophageal reflux
• History of seizures
• Neonates
• Concommitant use with transcutaneous elecrtical 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
• Coadministrations with CYP2D6 ultra-rapid metabolisers

Cautions

• Pregnancy
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly 
• Debilitated
• 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

Doxylamine
Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Pregnancy 
• Breastfeeding 
• Epileptics 
• Severe cardiac disease 
• Acute asthma attack 

Cautions

• Elderly 
• Closed-angle glaucoma 
• Urinary retention 
• Hepatic impairment 
• Prostatic hypertrophy 
• Pyloroduodenal obstruction 
• Cardiac failure 
• Hypertension 
• Oedema 
• Cardiovascular disease 
• May impair ability to drive and operate machinery

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

Pain - mild to moderate
Fever

Paracetamol/ Caffeine/ Codeine/ Doxylamine
450/50/10/5 (mg)

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

450/45/10/5 (mg)

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

450/30/10/5 (mg)

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

Paed. forms avail. in SA and covered in this monograph: tab, eff

Pain - mild to moderate
Fever

Paracetamol/ Caffeine/ Codeine/ Doxylamine
450/50/10/5 (mg)
450/45/10/5 (mg)
450/30/10/5 (mg)

• Younger than 12 years: Not established for use
• Older than 12 years: See adult dosage

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

Pregnancy

• Caution (Caffeine, Codeine)
• Caffeine in animal studies, at high doses, was shown to be embryotoxic and teratogenic. These effects are not relevant with regard to short-term administration in the preterm infant population
• Codeine is 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
• A large amount of data on pregnant women indicates no malformative nor foetal/ neonatal toxicity of doxylamine

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
• Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation. Breastfeeding mothers of newborn infants treated with caffeine citrate should not ingest caffeine-containing foods, beverages or medicinal products containing caffeine
• In newborn infants born to mothers who consumed large quantities of caffeine prior to delivery, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate
• The molecular weight of doxylamine succinate is low enough that passage into breast milk can be expected. Excitement, irritability and sedation have been reported in nursing infants presumably exposed to doxylamine succinate through breast milk. Infants with apnoea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine resulting in worsening of their apnoea or respiratory conditions
• 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, Codeine)

GFR (ml/min)	Paracetamol Dose	Codeine Dose
> 50	No adjustment necessary	No adjustment necessary
10-50	500mg, 6hrly	Administer 75% of the recommended dose
< 10	500mg, 8hrly	Administer 50% of the recommended dose

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 (Codeine)
• Codeine: Lower initial doses or longer dosing intervals followed by careful titration are recommended

Porphyria Information

• Not yet classified (NC) (Doxylamine)

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

Caffeine
Central Nervous System Disorders

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

Cardiovascular Disorders

• Angina pectoris
• Chest pain
• Palpitations
• Flushing
• Sinus tachycardia
• Supraventricular tachycardia
• Vernticular arrhythmia
• Vasodilation

Gastrointestinal Disorders

• Oesophageal motility disorder
• Gastritis

Genitourinary Disorders

• Diuresis

Musculoskeletal Disorders

• Fasciculations

Skin and Subcutaneous Tissue Disorders

• Urticaria

Sensory Disorders

• Increased ocular 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

Doxylamine
Central Nervous System Disorders

• Sedation
• Lassitude
• Dizziness
• Incoordination
• Euphoria
• Depression
• Headache
• Irritability
• Nightmares
• Insomnia
• Nervousness
• Tremors
• Seizures
• Epileptiform seizures

Cardiovascular Disorders

• Hypotension
• Tachycardia

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Anorexia
• Increased appetite
• Epigastric pain

Genitourinary Disorders

• Difficulty in micturition
• Dysuria

Musculoskeletal Disorders

• Muscular weakness

Immune, Blood and Lymphatic System Disorders

• Allergic reactions
• Agranulocytosis
• Leucopenia
• Haemolytic anemia

Sensory Disorders

• Blurred vision
• Tinnitus

Others

• Dryness of the mouth
• Tightness of the chest

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
• Sympathomimetics
• Xanthines

Codeine

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

Doxylamine

• Central nervous system depressants
• Monoamine oxidase inhibitors
• Antimuscarinic agents
• Ototoxic agents

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.

Doxylamine
Doxylamine is a competitive histamine H1 antagonist.  It has sedative and anticholinergic properties.  

COMBINATION PREPARATIONS

Paracetamol/ Caffeine/ Codeine/ Doxylamine

Tablet 450mg/30mg/10mg/5mg

• Abflex-4 (Cipla)
• Acurate (Teva Pharmaceuticals)
• Adco-Paxidal (Adcock)
• Alpha-Dol (Be-tabs)
• Codoxol (Ranbaxy)
• Doxy Co (Gulf)
• Lenapain (Pharmacare)
• Nomopain (Lebasi Pharmaceuticals)
• Resdol (Adcock)
• Sedapain (Litha Pharma)
• Sedinol (Pharmacare)
• Syndol  (Adcock) originator
• Tensopyn (Mirren)
• Tensodol (Cipla Medpro)

Tablet 450mg/45mg/10mg/5mg

• Adco-dol (Adcock)
• Pynstop (Adcock)

Tablet  450mg/50mg/10mg/5mg

• Betapyn (Adcock)

Tablet  500mg/30mg/10mg/5mg

• B-Dol (Be-Tabs)
• Pharmadol (Medicine)

Tablet effervescent 450mg/50mg/10mg/5mg

• Tensopyn Eft (Cipla Medpro)