Ammonium/ Diphenhydramine/ Codeine

Registered South African indications:

• Cough

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

Ammonium
Contraindications

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

Cautions

• Pregnancy
• Breastfeeding
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Respiratory insufficiency

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
• Myasthenia gravis
• Epilepsy
• Bronchitis
• Chronic obstructive pulmonary disease
• Tinnitus
• Prolonged use
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

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 
• 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

Additional contraindications for this combination product

• Monoamine oxidase inhibitors or within 14 days of their use

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

Relief of cough

Ammonium/ Diphenhydramine/ Codeine
125/12.5/10 (mg/5ml)

• Oral (syr): 5-10ml, 4hrly; Max: 4 doses/24hrs

100/12/7.5 (mg/5ml)

• Oral (syr): 10ml, 4hrly

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

Relief of cough

Ammonium/ Diphenhydramine/ Codeine
125/12.5/10 (mg/5ml)

Younger than 6 years

• Not established for use

Older than 6 years

• Oral (syr): 2.5-5ml, 4hrly; Max: 4 doses/24hrs

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

Pregnancy

• Caution (Ammonium chloride, Codeine, Diphenhydramine)
• The safety of ammonium chloride during pregnancy has not been established, although there is no good evidence of an association between first-trimester exposure to ammonium chloride  and foetal abnormalities
• 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
• Diphenhydramine crosses the placenta. Because animal reproduction studies are not always predictive of human response and since there is inadequate experience with the use of diphenhydramine in pregnant women, the potential risk for humans is unknown. Use of sedating antihistamines during the third trimester may result in reactions in the newborn or premature neonates. This agent is not recommended during pregnancy

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

Renal Impairment

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

GFR (ml/min)	Codeine 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 (Ammonium chloride)

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 (Ammonium, 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) (Ammonium chloride, Diphenhydramine)

Drugs in Sport

• Permitted - No warnings

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

Ammonium
Central Nervous System Disorders

• Coma
• Confusion
• Seizures
• Fever  

Gastrointestinal Disorders

• Gastrointestinal discomfort
• Nausea and vomiting

Diphenhydramine
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

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

Ammonium

• Potassium sparing diuretics

Diphenhydramine

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

Codeine

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

None routine. Specific cases may require

• Hepatic function
• Respiratory function

Ammonium
Ammonium chloride is used as an expectorant. It causes irritation of the bronchial mucosa, which results in the production of excess respiratory tract fluid. This allows for easier mucus expulsion due to its decreased viscosity. 

Diphenhydramine
Diphenhydramine is a histamine H1-receptor 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. 

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

Ammonium/ Diphenhydramine/ Codeine

Syrup (per 5ml) 125mg/12.5mg/10mg

• Benylin with Codeine (Johnson&Johnson) originator
• Expectalin with Codeine (Johnson&Johnson) originator

Syrup (per 5ml) 100mg/12mg/7.5mg

• Flutex Co Linctus (Aspen)