Guaifenesin/ Pseudoephedrine/ Codeine/ Triprolidine

Registered South African indications:

• Cough

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

Guaifenesin
Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Children younger than 6 years

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Chronic or persistent cough

Pseudoephedrine
Contraindictions

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Severe renal impairment
• Cardiovascular disease
• Children younger than 12 years
• Phaeochromocytoma
• Diabetes mellitus
• Hyperthyroidism
• Closed angle glaucoma
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use
• Coadministration with other sympathomimetic decongestants
• Coadministration with beta blockers

Cautions

• Breastfeeding
• Mild to moderate renal impairment
• Severe hepatic impairment
• Elderly
• Enlarged prostate
• Bladder dysfunction
• Seizure disorders

Codeine
Contraindications

• Hypersensitivity to the active ingredient or to 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 
• 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

Triprolidine
Contraindications

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

Cautions

• Pregnancy 
• Breastfeeding
• Children
• Pulmonary insufficiency
• Prostatic hypertrophy  
• Glaucoma
• May impair ability to drive and operate machinery

Additional contraindications for the combination product

• Hypertension

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

Relief of cough

Guaifenesin/ Pseudoephedrine/ Codeine/ Triprolidine
100/20/7.5/1.25 (mg/5ml)

• Oral (syr): 5-10ml, 8hrly

Paed. forms avail. in SA and covered in this monograph: syr

Relief of cough

Guaifenesin/ Pseudoephedrine/ Codeine/ Triprolidine

50/12/3/0.6 (mg/5ml)

• Younger than 6 years: Not established for use
• Between 2-5 years: Oral (syr): 2.5-5ml, 8hrly
• Between 6-12 years: Oral (syr): 5-10ml, 8hrly
• Older than 12 years: See adult dosages

100/20/7.5/1.25 (mg/5ml)

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

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

Pregnancy

• Caution (Guaifenesin, Pseudoephedrine, Codeine, Triprolidine)
• There are no or limited amount of data from the use of guaifenesin in pregnant women. As a result, guaifenesin is not recommended during pregnancy or in women of childbearing potential not using contraception
• The safety of pseudoephedrine during pregnancy  has not been established but in view of a possible association of foetal abnormalities with first-trimester exposure to pseudoephedrine, the use of the product during pregnancy should be avoided
• 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

• Systemic administration of triprolidine in rats and rabbits up to 75 times the human dose did not produce teratogenic effects. Caution should be exercised by balancing the potential benefit of treatment to the mother against any possible hazards to the developing foetus

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
• It is unknown whether guaifenesin/ metabolites are excreted in human milk, therefore, a risk to newborns/ infants cannot be excluded. As a result, guaifenesin is not recommended during breastfeeding
• The safety of pseudoephedrine during breastfeeding has not been established. The amounts of pseudoephedrine secreted into breast milk are considered to be too small to be harmful
• Triprolidine is excreted in breast milk in small amounts but the effect of this on breastfed infants is not known

Renal Impairment

• Mild to moderate: Caution; dose adjustment recommended (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

• Severe: Contraindicated (Pseudoephedrine)

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended (Codeine)
• There are no dosage adjustments provided in the manufacturer's labelling, however, lower initial doses or longer dosing intervals followed by careful titration are recommended
• Severe: Contraindicated (Codeine)

Elderly

• Caution; dose adjustment recommended (Codeine)
• Lower initial doses or longer dosing intervals followed by careful titration are recommended

Porphyria Information

• Not yet classified (NC) (Guaifenesin, Triprolidine)

Drugs in Sport

• Prohibited - In competition

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

Guaifenesin
Central Nervous System Disorders

• Dizziness
• Drowsiness
• Headache

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting

Genitourinary Disorders

• Nephrolithiasis

Endocrine and Metabolic Disorders

• Hypouricemia

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Urticaria 
• Rash

Pseudoephedrine
Central Nervous System Disorders

• Hallucinations
• Insomnia
• Anxiety
• Restlessness
• Irritability
• Psychosis
• Headache
• Seizures
• Vertigo
• Ataxia
• Fatigue 
• Tremor

Cardiovascular Disorders

• Tachycardia
• Palpitations
• Arrhythmias
• Hypertension
• Impaired circulation to the extremities

Respiratory Disorders

• Dry throat
• Dry nose
• Dyspnoea
• Nasal congestion
• Pharyngeal oedema
• Thickening of bronchial secretions
• Wheezing

Gastrointestinal Disorders

• Dry mouth
• Nausea and vomiting
• Anorexia
• Constipation
• Diarrhoea
• Ischemic colitis

Genitourinary Disorders

• Urinary retention
• Dysuria

Skin and Subcutaneous Tissue Disorders

• Diaphoresis
• Skin photosensitivity
• Skin rash
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Anaphylaxis
• Agranulocytosis
• Haemolytic anaemia
• Thrombocytopaenia

Sensory Disorders

• Closed angle glaucoma
• Blurred vision
• Diplopia
• Tinnitus

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

Triprolidine
Skin and Subcutaneous Tissue Disorders 

• Lichenoid skin eruption

Sensory Disorders

• Masking of warning signs of ototoxic damage

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

Guaifenesin

• Cough suppressants

Pseudoephedrine

• Sympathomimetic agents
• Antihypertensive agents
• Monoamine oxidase inhibitors
• Volatile anaesthetics
• Cardiac glycosides
• Anticholinergic agents
• Antidepressants
• Antipsychotics 
• Doxapram 
• Oxytocin
• Aluminium oxide 

Codeine

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

Triprolidine

• Central nervous system depressants
• Anticholinergic agents
• Agents increasing serum potassium 
• Secretin 

None routine

Guaifenesin
The exact mechanism of action of guaifenesin is unknown. It may act by irritating gastric vagal receptors resulting in the activation of efferent parasympathetic reflexes, which cause glands to secrete less viscous mucous. This may help to clear small airways obstructed by congealed mucous. 

Pseudoephedrine
Pseudoephedrine acts mainly on alpha and also on beta adrenergic receptors. It produces vasoconstriction by acting on the alpha adrenergic receptors in the mucosa of the respiratory tract. This results in the decongestant properties of pseudoephedrine. 

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.

Triprolidine
Triprolidine provides symptomatic relief in conditions believed to depend wholly or partly upon the triggered release of histamine.  It is a potent competitive histamine H1-receptor antagonist of the pyrrolidine class with mild central nervous system depressant properties.

COMBINATIONS PREPARATIONS 

Guaifenesin/ Pseudoephedrine/ Codeine/ Triprolidine

Syrup (per 5ml) 50mg/12mg/3mg/0.6mg

• Acutussive Paed Expect (Pharmascript)
• Adco Neofed Paediatric (Adcock Ingram)
• Flusin junior Cough Syrup (Pharmacare)
• Linctifed wet cough children's syrup (GSK) originator
• Trifen Expectorant Paediatric (Ranbaxy Pharmaceuticals)

Syrup (per 5ml) 100mg/20mg/7.5mg/1.25mg

• Acutussive expect adult (Pharmascript)
• Linctifed wet cough (GSK) originator
• Trifen Expectorant Adult (Ranbaxy Pharmaceuticals)