DATA SHEET

Codeine phosphate tablets

Codeine phosphate as 15 mg, 30 mg and 60 mg tablets.

Presentation

Codeine phosphate 15 mg, 30 mg and 60 mg tablets are white, circular, film-coated

tablets embossed with 'DP' on one side and '15', '30' and '60' respectively on the other.

Uses

Actions

Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is
much less potent as an analgesic and has only mild sedative effects. Its primary site of
action is at the mu opioid receptors distributed throughout the central nervous system.

Codeine phosphate reduces intestinal motility through both a local and possibly central
mechanism of action. Codeine phosphate also suppresses the cough reflex by a direct
central action, probably in the medulla or pons.

Codeine and its salts are absorbed from the gastro-intestinal tract and onset of
analgesic action occurs 30 to 45 minutes after administration, when given orally.

Peak effect is reached within 1 to 2 hours and the duration of analgesic and antitussive
action are 4 hours and 4 to 6 hours respectively.

Pharmacokinetics

Codeine is readily absorbed from the gastro-intestinal tract and metabolised by O- and
N-demethylation in the liver to morphine and norcodeine which with codeine are
excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

Most of the excretion products appear in the urine within 6 hours and 40 to 60 per cent
of the codeine is excreted free or conjugated, approximately 5 to 15 per cent as free
and conjugated morphine and about 10 to 20 per cent as free and conjugated
norcodeine.

Indications

Codeine phosphate is indicated for:

the relief of mild to moderate pain (including pain associated with terminal illness,
post-operative pain and headache),
the relief of symptoms of diarrhoea (except diarrhoea caused by poisoning),
 as an antitussive in the control of non-productive cough.

Codeine is particularly valuable for pain associated with coughing.

Dosage and administration

Adults
Codeine phosphate may be given orally in doses of 15 mg 60 mg up to 6 times a day
for the relief of pain. If these doses fail to relieve pain, larger doses rarely succeed and
may give rise to restlessness and excitement. The maximum recommended daily dose
is 300 mg.

For non-productive cough the usual dose is 10 mg 20 mg every 4-6 hours to a

maximum total of 120 mg in 24 hours.

Paediatric
The usual paediatric dose for analgesia in infants and children is 0.5 mg per kg of body
weight or 15 mg per square meter of body surface, every 4 to 6 hours as needed.

For cough children may be given up to 0.25 mg per kg every 4 - 6 hours.

On the basis of available data, codeine and other opioid cough suppressants should
rarely be administered to children less than 6 to 12 months old. They should not be
given in productive cough. When indicated for the treatment of non-productive cough,
which interferes with sleep or school attendance, codeine may be recommended in the
form of single-ingredient preparations.

Contraindications
Known hypersensitivity to codeine, other opioids or any component of the tablets
Acute respiratory depression (especially in the presence of cyanosis and excessive
bronchial secretion)
Obstructive airways disease
Acute alcoholism
Head injuries or conditions in which intracranial pressure is raised
Patients at risk of paralytic ileus
Hepatic failure
Acute asthma attack
Heart failure secondary to chronic lung disease
Diarrhoea associated with pseudomembranous colitis or diarrhoea caused by
poisoning
Patients taking monoamine oxidase inhibitors or within 14 days of stopping such
treatment.

Warnings and precautions

Codeine phosphate should be used with caution in patients with the following
conditions:
Hypothyroidism
 Adrenocortical insufficiency e.g. Addisons Disease
Impaired kidney/liver function
Prostatic hypertrophy
Shock/ hypotension
Myasthenia gravis
Convulsions/ convulsive disorders
Gall bladder disease or gall stones
Recent gastro-intestinal surgery
Urinary tract surgery
Reduced respiratory function or history of asthma
Obstructive and inflammatory bowel disease codeine reduces peristasis,
increases tone and segmentation in the bowel and can raise colonic pressure.
Patients taking monoamine oxidase inhibitors or within 14 days of stopping such
treatment.

Hypersensitivity Maculopapular rash, fever, splenomegaly and lymphadenopathy

have been seen as part of a codeine hypersensitivity reaction.

Dependence taking codeine regularly for a long time can lead to addiction. Stopping
treatment can result in withdrawal symptoms. Codeine is not a satisfactory substitute
for patients dependent on morphine. Regular use of analgesics for headache can
result in an overuse syndrome.

Withdrawal abrupt withdrawal precipitates a withdrawal syndrome. Symptoms may

include tremor, insomnia, restlessness, irritability, anxiety, depression, anorexia,
nausea, vomiting, diarrhoea, sweating, lacrimation, rhinorrhoea, sneezing, yawning,
piloerection, mydriasis, weakness, pyrexia, muscle cramps, dehydration and increase
in heart rate, respiratory rate and blood pressure. These effects can also occur in
neonates exposed to codeine in utero (see use in pregnancy).

Tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove
fatal.

Genetic polymorphism Codeine is metabolised to morphine by cytochrome P450

2D6. Some patients are ultra-rapid metabolisers and are at higher risk of toxic opioid
effects. Some patients are slow metabolisers and these patients may not experience
adequate analgesic effect with codeine.

Use in Pregnancy The balance of benefits and risks should be carefully considered
because opioid analgesics cross the placenta. Regular use during pregnancy may
cause physical dependence in the foetus, leading to withdrawal symptoms
(convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting,
diarrhoea, sneezing and yawning) in the neonate. Prolonged high-dose use of Codeine
prior to delivery may produce Codeine withdrawal symptoms in the neonate.

Although teratogenic effects in humans have not been done, studies in animals have
not shown codeine to cause adverse effects on foetal development. Studies in animals
have shown codeine (single dose of 100 mg per kg) to cause delayed ossification in
mice and (in doses of 120 mg per kg) increased resorption in rats.
Use during Lactation - Codeine is excreted into breast milk. However with usual
analgesic doses, concentrations are generally low.

However, infants of nursing mothers taking codeine may have an increased risk of
morphine overdose if the mother is an ultra-rapid metaboliser of codeine. Nursing
mothers taking codeine, who are ultra-rapid metabolisers, may have higher morphine
levels in their breast milk, which may lead to life-threatening or fatal side effects in
nursing babies.

When prescribing codeine for a nursing mother, the lowest dose for the shortest
amount of time to relieve pain or cough should be prescribed. Nursing patients should
be told how to recognize signs of high morphine levels in themselves and their babies.

Signs of high morphine levels in a mother are extreme sleepiness and trouble caring
for the baby.

Breastfed babies usually nurse every two to three hours and should not sleep more
than four hours at a time. If the baby shows signs of increased sleepiness (more than
usual), difficulty breastfeeding, breathing difficulties, or limpness, the mother should
immediately seek medical advice.

Use in children Children up to 2 years of age may be more susceptible to the effects,
especially the respiratory depressant effects of opioid analgesics. Paradoxical
excitation is especially likely to occur in paediatric patients receiving these medicines.

Use in the Elderly - Geriatric patients may be more susceptible to the effects,
especially the respiratory depressant effects, of these medications. Also geriatric
patients are more likely to have prostatic hypertrophy or obstruction and age-related
renal function impairment, and are therefore more likely to be adversely affected by
opioid-induced urinary retention. The risk of constipation and faecal impaction is also
greater in the elderly.

Geriatric patients may metabolize or eliminate opioid analgesics more slowly than
younger adults. Lower doses or longer dosing intervals than those usually
recommended for adults may be required, and are usually therapeutically effective for
these patients.

Effects on ability to drive and use machines - codeine may cause drowsiness or a
decrease in alertness in some patients. Patients should be cautioned about operating
vehicles or machinery, or engaging in activities which require them to be fully alert.

Adverse effects

Immune system disorders rash, urticaria, pruritus, difficulty breathing, increased

sweating, redness of flushed face, angioedema

Nervous system disorders confusion, drowsiness, malaise, tiredness, vertigo,

dizziness, changes in mood, hallucinations, CNS excitation (restlessness/excitement),
convulsions, mental depression, headache, nightmares, raised intracranial pressure,
tolerance or dependence, dysphoria, hypothermia
Eye Disorders miosis, blurred or double vision

Cardiac Disorders bradycardia, palpitations, hypotension, orthostatic hypotension,

tachycardia

Respiratory, thoracic and mediastinal disorders- respiratory depression

Gastrointestinal Disorders constipation, biliary spasm, nausea, vomiting, dry mouth

Musculoskeletal, connective tissue and bone disorders muscle rigidity

Renal and Urinary Disorders ureteral spasm, anti-diuretic effect, urinary retention

Reproductive system and Breast Disorders- decrease in libido and potency

Withdrawal effects abrupt withdrawal precipitates a withdrawal syndrome.

Symptoms may include tremor, insomnia, restlessness, irritability, anxiety, depression,
anorexia, nausea, vomiting, diarrhoea, sweating, lacrimation, rhinorrhoea, sneezing,
yawning, piloerection, mydriasis, weakness, pyrexia, muscle cramps, dehydration and
increase in heart rate, respiratory rate and blood pressure.

Tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove
fatal.

Regular prolonged use of codeine is known to lead to addiction and tolerance.

Prolonged used of a painkiller for headaches can make them worse.

Interactions

Monoamine Oxidase Inhibitors due to the possible risk of excitation or

depression, avoid concomitant use and for 14 days after discontinuation of MAOI
Alcohol enhanced sedative and hypotensive effect, increased risk of respiratory
depression
Hypnotics and anxiolytics enhanced sedative effect, increased risk of respiratory
depression
Anticholinergics risk of severe constipation which may lead to paralytic ileus
and/or urinary retention
Metoclopramide and domperidone antagonistic effect on GI activity
Anti-diarrhoeal drugs increased risk of severe constipation
Anaesthetics enhanced sedative and hypotensive effect
Tricyclic antidepressants enhanced sedative effect
Antipsychotics enhanced sedative and hypotensive effect
Opioid antagonists may precipitate withdrawal symptoms
Quinidine reduced analgesic effect
Antihypertensive drugs enhanced hypotensive effect
Ciprofloxacin avoid premedication with opioids as they reduce ciprofloxacin
concentration
Ritonavir may increase plasma levels of opioid analgesics
 Mexiletine delayed absorption of mexiletine
Cimetidine inhibits the metabolism of opioid analgesics causing increased plasma
codeine concentrations

Overdosage

Symptoms: Poisoning with codeine produces central stimulation and exhilaration and,
in children, convulsions, followed by vomiting, drowsiness, respiratory depression and
cyanosis, and coma. Death may occur from respiratory failure.

Toxic doses vary considerably with the individual and regular users may tolerate larger
doses.

Treatment: The stomach should be emptied by aspiration or lavage. A laxative may be

given to aid peristalsis. Intensive supportive therapy may be required to correct
respiratory failure and shocks. In addition, the specific antagonist naloxone
hydrochoride is used to counteract very rapidly the severe respiratory depression and
coma produced by excessive doses of opioid analgesics. A dose of 0.4 mg to 2 mg is
given intravenously, intramuscularly or subcutaneously, repeated at intervals of 2 to 3
minutes if necessary, up to 10 mg. The effect of naloxone may be of shorter duration
than that of the opioid analgesic and additional doses may be required to prevent
relapses.

The use of opioid antagonists such as naloxone, nalorphine and levallorphan in

persons physically dependant on opioid agonists may induce withdrawal symptoms.

Pharmaceutical precautions

Protect from light and moisture. Store below 30 C. Keep out of reach of children.

Medicine classification

Controlled Drug C2.

Package quantities

Codeine 15mg: 100's

Codeine 30mg: 100's
Codeine 60mg: 100's

Further information

Codeine is obtained from opium or made by methylating morphine. It occurs as

odourless colourless crystals or white crystalline powder. Codeine phosphate has a
molecular formula and weight of C18H21NO3, H3PO4, H2O and 406.37 respectively.

Codeine phosphate tablets distributed by Douglas Pharmaceuticals Ltd are not

substitutable with any other brands of codeine phosphate tablets.
Other ingredients of the tablets are: Lactose, Maize Cornflour, microcrystalline
cellulose, Sodium Starch Glycolate, Magnesium Stearate, Polyvinylpyrrolidinone K30
and Opadry White Y-1-7000B.

Name and address

Douglas Pharmaceuticals Ltd

P.O. Box 45-027
AUCKLAND 0651

Ph: (09) 835-0660

Fax: (09) 835-0665

Date of preparation

March 2011