Naloxone Hydrochloride 400 Micrograms/Ml Solution For Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Naloxone Hydrochloride 400 micrograms/ml solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ampoule of 1 ml contains 440 micrograms Naloxone hydrochloride as dihydrate, equivalent to 400 micrograms Naloxone hydrochloride.
Each 1 ml ampoule also contains 3.5 mg (0.154 mmol) of sodium.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection.
Clear colourless solution. pH 3.0 to 4.5
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Naloxone is indicated for the treatment of respiratory depression induced by natural and synthetic opioids, such as codeine, diamorphine, levorphanol, methadone, morphine, concentrated opium alkaloid hydrochlorides and propoxyphene. It is also useful for the treatment of respiratory depression caused by opioid agonist/ antagonists nalbuphine and pentazocine. Naloxone is also used for the diagnosis of suspected acute opioid overdose.
4.2 Posology and method of administration
Naloxone hydrochloride may be administered by IV, IM or SC injection or IV infusion.
Adults:
For instructions on preparation see section 6.6.
Naloxone hydrochloride may be used postoperatively to reverse central depression resulting from the use of opioids during surgery. The usual dosage is 100 - 200 micrograms IV given at 2 to 3 minute intervals to obtain optimum respiratory response while maintaining adequate analgesia. Additional doses may be necessary at one to two hour intervals depending on the response of the patient and the dosage and duration of action of the opioid administered.
For the treatment of known opioid overdosage or as an aid in the diagnosis of suspected opioid overdosage, the usual initial adult dosage of naloxone hydrochloride is 400 - 2000 micrograms IV, administered at 2 to 3 minute intervals if necessary. If no response is observed after a total of 10 mg of the drug has been administered, the depressive condition may be caused by a drug or disease process not responsive to naloxone. When the IV route cannot be used, the drug may be administered by IM or SC injection.
Children:
The usual initial dose in children is 10 micrograms / kg bodyweight given IV. If the dose does not result in the desired degree of clinical improvement, a subsequent dose of 100 micrograms / kg body weight may be administered. If the IV route of administration is not available, naloxone may be administered IM or SC in divided doses. If necessary naloxone can be diluted with sterile water for injection.
Opioid - induced depression in neonates resulting from the administration of opioid analgesics to the mother during labour may be reversed by administering naloxone hydrochloride 10 micrograms / kg body weight to the infant by IM, IV or SC injections, repeated at intervals of 2 to 3 minutes if necessary. Alternatively, a single IM dose of about 60 micrograms / kg may be given at birth for a more prolonged action.
Elderly:
In elderly patients with pre-existing cardiovascular disease or in those receiving potentially cardiotoxic drugs, naloxone should be used with caution since serious adverse cardiovascular effects such as ventricular tachycardia and fibrillation have occurred in postoperative patients following administration of naloxone.
4.3 Contraindications
Hypersensitivity to naloxone or to any of the excipients.
4.4 Special warnings and precautions for use
When naloxone is used in the management of acute opioid overdose, resuscitation equipment (including other appropriate medication) should be readily available.
Naloxone should be administered with caution to patients who have received large doses of opioids or to those physically dependent on opioids since too rapid reversal may precipitate an acute withdrawal syndrome. Hypertension, cardiac arrhythmias, pulmonary oedema and cardiac arrest (with subsequent death, coma and encephalopathy) have been described. Withdrawal symptoms (including convulsions, excessive crying and hyperactive reflexes) may also be precipitated in newborn infants of opioid-dependent mothers.
Patients who have responded to naloxone should be carefully monitored for the recurrence of respiratory depression (and other signs/symptoms) since the duration of action of some opioids may exceed that of naloxone (average of 30 min by IV route). Repeated doses of naloxone may be required. The most appropriate criteria for monitoring are respiratory rate, minute volume, arterial pC02 and pupillary diameter. All patients should be observed for at least 6 hours after the last dose of naloxone.
Naxolone is not effective in central depression caused by other agents so possible concomitant intake of other medicines or drugs (alcohol, benzodiazepines and barbiturates) needs to be considered. Reversal of buprenorphine-induced respiratory depression may be incomplete (in such cases respiration should be mechanically assisted).
Following the use of opioids during surgery, excessive doses of naloxone should be avoided as this can cause clinically important reversal of analgesia. Abrupt postoperatively reversal may result in nausea, vomiting, sweating and/or tachycardia as well as the more serious effects of abrupt withdrawal (outlined elsewhere in section
4.4 & in section 4.8)
Cardiovascular disease or concomitant cardiotoxic drugs Patients with pre-existing cardiovascular disease or having received concomitant cardiotoxic drugs (eg cocaine, metamphetamine, cyclic antidepressants, calcium channel blockers, digoxin) are at particular risk of adverse cardiac effects (including hypertension, hypotension, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest).
Renal disease
Safety and efficacy of naloxone in patients with renal insufficiency failure has not been established in clinical trials, so additional caution is required.
Hepatic disease
Safety and efficacy of naloxone in patients with hepatic impairment has not been established in clinical trials. In one small study in patients with liver cirrhosis, plasma naloxone concentrations were six times higher than in patients without liver disease and naloxone had a diuretic effect in the patients with cirrhosis. Particular caution is therefore required in these patients.
Sodium content
This medicinal product contains 0.154 mmol (3.5 g) sodium per ml of solution for injection. This should be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
No drug or chemical agent should be added to naloxone unless its effect on the chemical and physical stability of the solution has first been established.
4.6 Fertility, pregnancy and lactation
Pregnancy
Reproductive studies in animals have not revealed evidence of teratogenicity or harm to the foetus. There are no adequate and controlled studies using the drug in pregnant women. Therefore, naloxone should be used only when clearly needed.
Lactation
Since it is not known whether naloxone is distributed into breast milk, the drug should be used with caution in nursing women.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
The following frequency terminology is used:
Very common: ^ 1/10;
Common: ^ 1/100, < 1/10;
Uncommon: ^ 1/1,000, < 1/100;
Rare: > 1/10,000, < 1/1,000;
Very rare: < 1/10,000;
Not known (cannot be estimated from the available data)
Nervous system disorders
Common: Headache Rare: Seizures
Cardiac disorders
Uncommon: Tachycardia Rare: Cardiac arrhythmia
Vascular disorders
Rare: Hypotension, hypertension
Hypotension, hypertension and cardiac arrhythmia have also occurred with the postoperative use with high dose of naloxone.
Adverse cardiovascular effects have occurred most frequently in postoperative patients with a pre-existing cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.
Respiratory, thoracic and mediastinal disorders
Very rare: Pulmonary oedema
Pulmonary oedema has also occurred with the postoperative use with high dose of naloxone.
Gastrointestinal disorders
Common: Nausea, vomiting
General disorders and administration site conditions
Uncommon: Opioid withdrawal syndrome
The signs and symptoms of opioid withdrawal syndrome may include but are not limited to the following: chills, nausea, vomiting, diarrhoea, anxiety, restlessness, irritability, sweating, shivering, tremor, tachycardia and increased blood pressure.
Rare: Post-operative pain, hyperventilation
Higher than recommended dosage in postoperative use can lead to the return of pain.
A fast reversal of opioid effect can induce hyperventilation.
4.9 Overdose
Features
None expected. There have been rare reports of hypertension, tachypnoea, pulmonary oedema, and ventricular fibrillation in patients with pre-existing heart disease. Naloxone may precipitate symptoms of withdrawal.
Management
Unlikely to be required. DO NOT give opioids to reverse adverse effects.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidotes ATC code: V03AB15
Naloxone hydrochloride is a semisynthetic (N-allylnoroxymorphine hydrochloride) opioid antagonist which is derived from thebaine. When administered in usual doses to patients who have not recently received opioids, naloxone exerts little or no pharmacologic effect. Even extremely high doses of the drug (10 times the usual therapeutic dose) produces insignificant analgesia, only slight drowsiness and no respiratory depression, psychotomimetic effects, circulatory changes or miosis.
In patients who have received large doses of diamorphine or other analgesic drugs with morphine-like effects, naloxone antagonises most of the effects of the opioid. There is an increase in respiratory rate and minute volume, arterial p CO2 decreases toward normal and blood pressure returns to normal if depressed. Naloxone antagonises mild respiratory depression cause by small doses of opioids. Because the duration of action of naloxone is generally shorter than that of the opioid, the effects
of the opioid may return as the effects of naloxone dissipates. Naloxone antagonises opioid-induced sedation or sleep. Reports are conflicting on whether or not the drug modifies opioid-induced excitement or siezures.
Naloxone does not produce tolerance or physical or psychological dependence. However, 0.4 mg of naloxone hydrochloride administered SC will precipitate potentially severe withdrawal symptoms in patients physically dependent on opioids or pentazocine. The precise mechanism of action of the opioid antagonist effects of naloxone is not known. Naloxone is thought to act as a competitive antagonist at p, K or a opioid receptors in the central nervous system. It is thought that the drug has the highest affinity for the p receptor.
5.2 Pharmacokinetic properties
Naloxone has an onset of action within 1 to 2 minutes following IV administration and within 2 to 5 minutes following SC or IM administration. The duration of action depends on the dose and route of adninistration and is more prolonged following IM administration than after IV administration. In one study, the duration of action was 45 minues following IV administration of naloxone hydrochloride 0.4 mg/70 kg.
Following administration of 35 or 70 micrograms of naloxone hydrochloride in the umbilical vein in neonates in one study, peak plasma naloxone concentrations occurred within 40 minutes and were 4 - 5.4 ng/ml and 9.2 - 20.2 ng/ml, respectively. After IM administration of 0.2 mg to neonates in the same study, peak plasma naloxone concentrations of 11.3 - 34.7 ng/ml occurred within 0.5 - 2 hours.
Following parenteral administration, naloxone is rapidly distributed into body tissues and fluids. In rats, high concentrations are observed in the brain, kidney, spleen, lungs, heart and skeletal muscles. In humans, the drug readily crosses the placenta. It is not known whether naloxone is distributed into milk.
The plasma half-life of naloxone has been reported to be 60 to 90 minutes in adults and about 3 hours in neonates.
Naloxone is rapidly metabolised in the liver, principally by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation. Limited studies with radiolabeled naloxone indicated that 25 - 40% IV doses of the drug is excreted as metabolites in urine in 6 hours, about 50% in 24 hours and 60 -70% in 72 hours.
5.3 Preclinical safety data
Not applicable since naloxone has been used in clinical practice for many years and its effects in man are well known.
6.1 List of excipients
Sodium Chloride
Sodium Hydroxide (for pH-adjustment) Hydrochloric Acid (for pH-adjustment) Water for Injection
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
3 years
Shelf life after first opening :
After first opening the medicinal product should be used immediately.
Shelf-life after dilution :
Chemical and physical in-use stability has been demonstrated for 48 hours below 20°C.
From the microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store the ampoule in the outer carton until used to protect from light.
Please refer to section 6.3 for storage of the product that have been diluted.
6.5 Nature and contents of container
The product is contained in a glass ampoule (Type I) of 1ml. In boxes of 10 ampoules.
6.6 Special precautions for disposal
Naloxone may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone in 500 ml of either solution provides a concentration of 4 micrograms /ml. Infusion should be commenced as soon as practicable after preparation of the mixture in order to reduce microbiological hazards.. The rate of administration should be titrated in accordance with the patient's response. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Laboratoire AGUETTANT 1, rue Alexander Fleming 69007 Lyon France
Distributed by :
AGUETTANT Ltd. Cleeve Somerset BS49 4NF
8 MARKETING AUTHORISATION NUMBER(S)
PL 14434/0021
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/02/2011
10 DATE OF REVISION OF THE TEXT
19/02/2013