Codeine Phosphate-Promethazine HCl

Uses

Codeine is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated.

Codeine sulfate is a form of this drug that is commonly used. It is available in tablet form and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate .

The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above , .

Promethazine Theoclate Tablets are an anti-emetic (anti-sickness drug) which helps to prevent, and treat nausea and vomiting, including travel sickness, and vertigo. Promethazine Theoclate contains promethazine which belongs to a group of medicines called phenothiazines. Your doctor may prescribe this medicine for giddiness or light-headedness (vertigo), or for sickness after an operation, and in such cases the tablets should be taken as instructed by your doctor.

Codeine Phosphate-Promethazine HCl is also used to associated treatment for these conditions: Common Cold, Cough, Flu caused by Influenza, Mild pain, Pain, Severe Pain, Dry cough, Moderate Pain, Upper respiratory symptoms, Airway secretion clearance therapyAllergic urticaria, Anaphylaxis, Cough, Dermographism, Motion Sickness, Nasal Congestion, Postoperative pain, Seasonal Allergic Conjunctivitis, Seasonal Allergic Rhinitis, Vasomotor Rhinitis, Acute Allergic Reactions, Dry cough, Perioperative nausea and vomiting, Upper respiratory symptoms, Sedative therapy, Adjunct to anesthesia and analgesia

How Codeine Phosphate-Promethazine HCl works

Codeine is a selective agonist for the mu opioid receptor, but with a much weaker affinity to this receptor than morphine, a more potent opioid drug. Codeine binds to mu-opioid receptors, which are involved in the transmission of pain throughout the body and central nervous system , . The analgesic properties of codeine are thought to arise from its conversion to Morphine, although the exact mechanism of analgesic action is unknown at this time , .

Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting.

Dosage

Codeine Phosphate-Promethazine HCl dosage

To prevent travel sickness on short journeys: Promethazine Theoclate should be taken at least one or two hours before travelling. Adults and children aged over 10 yearsshould take one tablet. Children aged 5 to 10 years should be given half a tablet.

To prevent travel sickness onlong journeys: Promethazine Theoclate should be taken at bedtime each night during the journey, startingthe night before you travel.Adults and childrenaged over 10 yearsshould take one tablet.Children aged 5 to 10 years should be given half a tablet.

To treat travel sickness:Adults and children over 10 years should take one tablet as soon as you feel sick, followed by a second tablet the same evening. Take a third tablet the following evening if necessary. Children aged 5 to 10 years should treated in the same way, but with half a tablet each time.

For sickness and vomiting due to other causes, and for treating vertigo: Adults and children aged over 10 years should take one tablet up to three times aday. Children aged 5 to 10 years should be given half a tablet up to three times a day.Alternativelyyou should follow the instructions given by your doctor.

Side Effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with promethazine. Just because a side effect is stated here does not mean that all people using Promethazine Theoclate will experience that or any side effect.

• Drowsiness or feeling tired.
• Dizziness.
• Restlessness.
• Headache.
• Nightmares.
• Blurred vision.
• Difficulty passing urine.
• Dry mouth.
• Confusion.
• Feeling disorientated.
• Unexpected increase in excitability in children.
• Increased sensitivity of the skin to sunlight (photosensitivity). If affected you should avoid sun lamps and direct sunlight while you are taking this medicine.
• Loss of appetite.
• Awareness of your heartbeat (palpitations).
• Abnormal heartbeats (arrhythmias).
• Low blood pressure (hypotension).
• Abnormal movements of the hands, legs, face, neck and tongue, eg tremor, twitching, rigidity (extrapyramidal effects).
• Blood disorders.

Toxicity

Oral LD50: 427 mg kg-1 (rat) .

Overdose/toxicity

Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal , .

Teratogenic effects

This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus .

Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose . Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison .

Nonteratogenic effects

Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment .

Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0.8 times the maximum recommended human dose of 360 mg/day .

The use in breastfeeding/nursing

Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants .

The intraperitoneal LD₅₀ in rats is 170mg/kg and in mice is 160mg/kg. The subcutaneous LD₅₀ in rats is 400mg/kg and in mice is 240mg/kg. The oral LD₅₀ in mice is 255mg/kg.

Patients experiencing an overdose of promethazine may present with mild central nervous system and cardiovascular depression, hypotension, respiratory depression, unconciousness, hyperreflexia, hypertonia, ataxia, athetosis, extensor-plantar reflexes, convulsions, dry mouth, flushing, gastrointestinal symptoms, and fixed, dilated pupils. Treat overdoses with symptomatic and supportive treatment, which may include activated charcoal, sodium sulfate, magnesium sulfate, controlled ventilation, diazepam, intravenous fluids, vasopressors, norepinephrine, phenylephrine, anticholinergic antiparkinsonian agents, diphenhydramine, barbiturates, or oxygen.

Precaution

Promethazine Theoclate tablets can make some people feel drowsy, dizzy, confused or disorientated and this may reduce your ability to drive or operate machinery safely. Do not drive or operate machinery until you know how this medicine affects you and you are sure it won't affect your performance. If your child is affected in this way they should avoid potentially hazardous activities such as riding bikes. You should not leave your child unattended after giving them this medicine.

Avoid drinking alcohol while taking Promethazine Theoclate because this is likely to make the above effects more likely or worse.

Promethazine Theoclate tablets may make your skin more sensitive to sunlight than usual, so you should avoid exposing your skin to direct sunlight or sunlamps until you know how your skin reacts. If you can't avoid strong sunlight you should use a sunscreen lotion or make sure your skin is protected with clothing.

This medicine may interfere with some pregnancy tests, causing false negative or false positive results.

If you are due to have any skin prick tests to diagnose allergies you should stop taking Promethazine Theoclate at least 72 hours before the tests. This is because antihistamines can prevent or lessen the skin reactions that indicate an allergy, and so can make the test results unreliable.

Interaction

It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start taking Promethazine Theoclate. Similarly, check with your doctor or pharmacist before taking any new medicines while taking Promethazine Theoclate, to make sure that the combination is safe.

Promethazine Theoclate should not be taken by anyone who has taken a type of antidepressant called a monoamine oxidase inhibitor (MAOI), eg phenelzine, tranylcypromine, isocarboxazid, in the previous 14 days.

You are more likely to feel drowsy if you take Promethazine Theoclate with any of the following (which can also cause drowsiness):

• alcohol
• antipsychotic medicines, eg chlorpromazine
• barbiturates, eg phenobarbital
• benzodiazepines, eg diazepam, temazepam
• sedating antihistamines, eg chlorphenamine, brompheniramine, hydroxyzine
• sleeping tablets, eg zopiclone
• strong opioid painkillers, eg morphine, codeine, dihydrocodeine, tramadol
• tricyclic antidepressants, eg amitriptyline.

Volume of Distribution

Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues .

The volume of distribution of promethazine is approximately 970L or 30L/kg.

Elimination Route

Absorption

Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration .

Food Effects

When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine .

Steady-state concentration

The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours .

A 25mg dose of intramuscular promethazine reaches a C_max of 22ng/mL. Intravenous promethazine reaches a C_max of 10.0ng/mL, with a T_max of 4-10h, and an AUC of 14,466ng*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a C_max of 2.4-18.0ng/mL, with a T_max of 1.5-3h, and an AUC of 11,511ng*h/mL.

Half Life

Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours .

The elimination half life of promethazine is approximately 12-15h.

Clearance

Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study .

Renal impairment may decrease codeine clearance .

The intravenous clearance of promethazine is approximately 1.14L/min. The renal clearance of promethazine is 5.9mL/min and the renal clearance of promethazine sulfoxide is 90.4mL/min.

Elimination Route

About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine .

The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine .

An intravenous dose of promethazine is 0.64% eliminated in the urine as the unchanged parent drug, 0.02-2.02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide.

Pregnancy & Breastfeeding use

If you are pregnant you should not take Promethazine Theoclate without consulting your doctor first. Promethazine Theoclate should only be used during pregnancy if essential, and only if the expected benefit to the mother outweighs any potential risks to the developing baby. It should not be used during the last two weeks of pregnancy, because if taken during this time it may cause irritability or excitement in the baby after birth. Seek further medical advice from your doctor.

Small amounts of Promethazine Theoclate may pass into breast milk. This is not expected to be harmful to a nursing infant with occasional short-term use of Promethazine Theoclate, but there is a risk that it may cause drowsiness, irritability or excitement in a newborn baby. If you are breastfeeding you should not take Promethazine Theoclate without getting medical advice from your doctor first.

Contraindication

• Children under five years of age.
• People with reduced awareness, slow reactions or extreme drowsiness caused by medicines or illnesses that reduce activity in the central nervous system.
• People who have taken a type of medicine called a monoamine-oxidase inhibitor antidepressant (MAOI) in the past 14 days.
• Children and adolescents who have signs and symptoms suggestive of Reye's syndrome.
• People who are allergic to any ingredients of the tablets.
• Promethazine Theoclate tablets contain lactose and should not be taken by people with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Storage Condition

Store between 15-30° C. Protect from light.

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