Summary of medicine characteristics - MAGNESIUM SULFATE 10% W/V SOLUTION FOR INJECTION OR INFUSION
1 NAME OF THE MEDICINAL PRODUCT
Magnesium sulfate 10% w/v Solution for injection or infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 10 mL ampoule contains 1 g magnesium sulfate heptahydrate (100 mg/mL).
1 mL contains 0.41 mmol (9.97 mg = 0.82 mEq) magnesium anions.
1 g of magnesium sulfate heptahydrate provides 4.1 mmol (8.2 mEq) of elemental magnesium.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection or infusion, with a pH of between 5.5 and 7 and osmolality of
400 mOsm/kg approximately.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Magnesium sulfate 10% w/v solution is indicated in adults, adolescents and children for;
i) the treatment of magnesium deficiency in proven hypomagnesaemia
ii) the prevention and treatment of hypomagnesaemia in patients receiving total parenteral nutrition
Magnesium sulfate 10% w/v solution is indicated in parturients for;
i) the control and prevention of seizures in severe pre-eclampsia
ii) the control and prevention of recurrent seizures in eclampsia.
4.2 Posology and method of administration
Magnesium sulfate 10% w/v solution is to be administered by the intravenous route (see below for method of administration and section 4.4).
Posology
Dosage should be tailored according to the individual’s needs and responses and should be reduced in renal impairment. Plasma magnesium concentrations should be measured to determine the rate and duration of infusion and should be monitored throughout therapy.
1 g Magnesium sulfate heptahydrate = 98.6 mg or 8.2 mEq or 4.1 mmol Mg2+.
Treatment of magnesium deficiency in proven hypomagnesaemia
Adults:
Up to 400 mL Magnesium sulfate 10% w/v solution (corresponding to 160 mmol ~ 4 g Mg2+) should be administered by slow intravenous infusion over a period of up to five days and titrated to clinical need. The usual regimen is 80 – 120 mL Magnesium sulfate 10% w/v solution (corresponding to 32 – 48 mmol ~ 0.8 – 1.2 g Mg2+) in the first 24 hours followed by 40 – 60 mL Magnesium sulfate 10% w/v solution (corresponding to 16 – 24 mmol ~ 0.4 – 0.6 g Mg2+) per day for 3 or 4 days.
Children and adolescents:
Neonate
1 mL/kg Magnesium sulfate 10% w/v solution (corresponding to 0.4 mmol/kg ~ 0.01 g/kg Mg2+) every 6 – 12 hours as required, to be given by intravenous injection over at least 10 minutes.
Child 1 month – 11 years
0.5 mL/kg Magnesium sulfate 10% w/v solution (corresponding to 0.2 mmol/kg ~ 0.005 g/kg Mg2+) every 12 hours as required, to be given by intravenous injection over at least 10 minutes.
Adolescent 12–17 years
10 mL Magnesium sulfate 10% w/v solution (corresponding to 4 mmol ~ 0.1 g Mg2+) every 12 hours as required, to be given by intravenous injection over at least 10 minutes.
Elderly:
There are no specific recommendations for dosage in elderly adults. Magnesium sulfate 10% w/v solution should be used with caution in elderly because of often renal impairment in this age group.
Prevention of hypomagnesaemia in patients receiving total parenteral nutrition
Adults:
25 – 50 mL Magnesium sulfate 10% w/v solution (corresponding to 10 – 20 mmol ~ 0.25 – 0.5 g Mg2+) daily, usual dose 30 mL Magnesium sulfate 10% w/v solution (corresponding to 12 mmol ~ 0.3 g Mg2+) daily, by intravenous infusion.
Neonates and infants (up to 12 months):
0.5 mL/kg Magnesium sulfate 10% w/v solution (corresponding to 0.2 mmol/kg = 0.005 g/kg Mg2+) daily by intravenous infusion.
Children (1 – 13 years) and adolescents (14 – 18 years):
0.25 mL/kg Magnesium sulfate 10% w/v solution (corresponding to 0.1 mmol/kg ~ 0.0025 g/kg Mg2+) daily by intravenous infusion.
Control and prevention of recurrent seizures in severe pre-eclampsia and eclampsia
Adult women:
Loading dose: An initial IV loading dose of approximately 40 – 50 mL Magnesium sulfate 10% w/v solution (corresponding to 16 – 20 mmol ~ 0.4 – 0.5 g Mg2+) diluted to an appropriate volume over 5 – 15 minutes is followed by a maintenance regimen of either an intravenous infusion of Magnesium sulfate 10% w/v solution, or regular IM injections using Magnesium sulfate 50% w/v solution for 24 hours after the last fit, provided respiratory rate is > 16/min, urine output > 25 mL/min and knee jerks are present, as follows:
IV Maintenance Regimen
The IV loading dose (above) is followed by an infusion of approximately 10 mL Magnesium sulfate 10% w/v solution (corresponding to 4 mmol ~ 0.1 g Mg2+) per hour for at least 24 hours after the last fit.
IM Maintenance Regimen
This concentration is not suitable for intramuscular use.
The IM injections are possible only using another, higher concentrated preparation (e.g. Magnesium sulfate 50% w/v solution).
The IV loading dose (above) is immediately followed by deep IM injection of 10 mL Magnesium sulfate 50% w/v solution (corresponding to 20 mmol ~ 0.5 g Mg2+).
Thereafter, 10 mL Magnesium sulfate 50% w/v solution (corresponding to 20 mmol ~ 0.5 g Mg2+) is administered every four hours IM, and continued for 24 hours after the last fit.
Recurrent convulsions: In both IV and IM regimens, a further 20 – 40 mL Magnesium sulfate 10% w/v solution (corresponding to 8 – 16 mmol ~ 0.2–0.4 g Mg2+) depending on body weight [if less than 70 kg 20 mL Magnesium sulfate 10% w/v solution (corresponding to 8 mmol ~ 0.2 g Mg2+)] are given IV over a period of 5 minutes.
Renal impairment
Magnesium sulfate 10% w/v solution is contraindicated in patients with severe renal impairment (see section 4.3)
Magnesium sulfate 10% w/v solution should be used with caution in mild to moderate renal impairment. A reduction in dosage to 200 mL Magnesium sulfate 10% w/v solution (corresponding to 80 mmol ~ 2 g Mg2+) over 48 hours may be given.
Patients with impaired liver function
There are no recommended special dosage instructions for patients with impaired liver function because of insufficient data.
Method of administration
For the intravenous route the 10% solution does not require dilution. Magnesium sulfate 10% w/v solution is not appropriate for intramuscular administration. Only the 50% w/v solution available may be used intramuscularly.
Intravenous use in children:
Rate of administration should not exceed 0.1 mL/kg/min Magnesium sulfate 10% w/v solution (corresponding to 0.04 mmol/kg/min ~ 0.001 g/kg/min Mg2+).
Use in adults and adolescents
Intravenous infusion: Infuse via a volumetric infusion device at a rate appropriate to the indication (see posology above).
Intravenous injection: Give by slow IV injection at a rate appropriate to the indication (see posology above).
Deep intramuscular injection:Magnesium sulfate 10% w/v solution is not recommended for intramuscular injection. However, when using the IV loading/IM maintenance regimen above, ensure that the 50% w/v solution is used undiluted or diluted to 25% w/v solution. If the total dose to be administered exceeds 5 mL, the injection volume should be divided between more than one deep muscular injection site.
4.3 Contraindications
Hypersensitivity to magnesium and its salts or to any of the excipients listed in section 6.1.
Hepatic encephalopathy, hepatic failure, renal failure.
Severe renal impairment (glomerular filtration rate under 25 mL/h), anuria.
Parenteral administration of the medicinal product is contraindicated in patients with heart block (class I-III) or myocardial damage and myasthenia gravis.
4.4 Special warnings and precautions for use
Magnesium salts should be administered with caution to patients with impaired renal function and appropriate dosage reduction should be made.
Magnesium sulfate should not be used in hepatic coma if there is a risk of renal failure.
Serum calcium levels should be routinely monitored in patients receiving magnesium sulfate.
The serum-magnesium-level should be monitored during the treatment (normal 0.65 –1.0 mmol).
Monitoring of the absence of respiratory depression: the breath rate should not be under 16 breaths/min.
The excretion of urine should not be under 25 mL/h, as it could lead to hypermagnesaemia (see sections 4.2 and 4.3).
The presence of the patellar reflex should be checked.
Administer with caution if flushing and sweating occurs.
An antidote of injectable calcium gluconate solution should be immediately available.
For the intravenous use in children the rate of administration should not exceed 0.1 mL/kg/min Magnesium sulfate 10% w/v solution (corresponding to 0.04 mmol/kg/min = 0.001 g/kg/min Mg2+) (see section 4.2).
Magnesium sulfate 10% w/v solution is not suitable for intramuscular use.
For the intramuscular route, use good clinical practice for intramuscular injections. The 50% w/v solution should be used undiluted or diluted to 25% w/v. Avoid muscles which are emaciated or atrophied. Avoid the dorsogluteal muscle and sciatic nerve. If the total dose to be administered exceeds 5 mL, the injection volume should be divided between more than one deep muscular injection site. Use caution in older or thin patients who may only tolerate up to 2 mL in a single injection. Do not use an injection site that has evidence of infection or injury. If repeating an intramuscular dose, rotate injection sites to avoid injury or discomfort to the muscles.
4.5 Interaction with other medicinal products and other forms of interaction Muscle relaxants
The action of non-depolarising muscle relaxants such as tubocurarine is potentiated and prolonged by parenteral magnesium salts.
Calcium channel blockers or diuretics
There is a risk of cardiopulmonary events when intravenous magnesium sulfate is used concomitantly with calcium channel blockers or diuretics (such as thiazides, nifedipine and furosemide). Profound hypotension has been reported with nifedipine.
Calcium salts
Calcium salts may reduce the efficacy of magnesium.
Digitalis glycosides
Magnesium salts should also be administered with caution to those patients receiving digitalis glycosides.
Neuromuscular blocking agents
Parenteral administration of magnesium salts may enhance the effects of neuromuscular blocking agents. The neuromuscular blocking effects of parenteral magnesium and aminoglycoside antibacterials may be additive.
CNS Depressants
When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with magnesium, their dosage should be adjusted with caution because of additive depressant effects of magnesium and the risk of respiratory depression.
4.6 Fertility, pregnancy and lactation
Pregnancy
As eclampsia may be life-threatening to mother and baby, magnesium sulfate may be administered in this condition.
Sufficient amount of magnesium may cross the placenta in mothers treated with high doses e.g. in pre-eclampsia, causing hypotonia and respiratory depression in newborns. When used in pregnant women, fetal heart rate should be monitored and use within 2 hours of delivery should be avoided.
Magnesium sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of magnesium sulfate for more than 5 to 7 days. If this medicinal product is used during pregnancy, the woman should be apprised of the potential hazard to the fetus.
Breastfeeding
Safety during breast feeding has not been established. Therefore, as with all medicinal products, it is not advisable to administer magnesium sulfate during lactation unless considered essential.
Fertility
Based on long-term experience, no effects of magnesium on male and female fertility are anticipated.
4.7 Effects on ability to drive and use machines
Magnesium sulfate 10% w/v solution is unlikely to affect the ability to drive or to operate machinery. However, some people may feel dizzy or drowsy when given Magnesium sulfate 10% w/v solution. The patient should be advised not to drive or operate machinery.
4.8 Undesirable effects
The frequency of undesirable effects is not known.
Immune system disorder:
Hypersensitivity reactions.
Excessive administration of magnesium leads to the development of symptoms of hypermagnesaemia which may include:
Metabolism and nutrition disorders
Electrolyte/fluid abnormalities (hypophosphataemia, hypertonic dehydration)
There have been isolated reports of maternal and fetal hypocalcaemia with high doses of magnesium sulfate.
Nervous system disorders
Respiratory depression
Nausea, vomiting, drowsiness and confusion
Coma
Slurred speech, double vision
Loss of tendon reflexes due to neuromuscular blockade
Cardiac disorders
Cardiac arrhythmias, cardiac arrest
ECG abnormal (prolonged PR, QRS and QT intervals), bradycardia
Vascular disorders
Flushing of the skin and hypotension due to peripheral vasodilatation
Musculoskeletal and connective tissue disorders
Muscle weakness
General disorders and administration site conditions
Thirst
Especially in patients with impaired renal function, there may be sufficient accumulation of magnesium sulfate to produce toxic effects.
Injection/infusion-related
Too rapid administration: Vasodilatation, reduced blood pressure
Local: may be irritant to veins; extravasation may cause tissue damage
Intramuscular: pain, redness, swelling or warmth at the injection site, drainage at the injection site, prolonged bleeding, cellulitis, sterile abscess, signs of an allergic reaction, such as difficulty breathing or facial swelling, injury to nearby structures (blood vessels, bones, or nerves), inadvertent intravascular or intra-ostial injection, tissue necrosis, poor absorption due to high injectate volume.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other mineral supplements, magnesium sulfate
ATC code: A12CC02
Magnesium is the second most abundant cation in intracellular fluid and is an essential body electrolyte.
The body contains about 25 g of magnesium (about 14 mmol per kg body weight), approximately 60% of which is found in the skeleton. The daily amount of magnesium required by an adult is of the order of 270 to 350 mg (about 11 to 14 mmol). Symptomatic hypomagnesaemia is associated with a deficit of 0.5 – 1.0 mmol/kg.
Mechanism of action
It is a cofactor in numerous enzyme systems and is involved in phosphate transfer, muscle contractility and neuronal transmission.
Clinical efficacy and safety
The normal concentration of magnesium in plasma is around 0.65 to 1.0 mmol/L. Serum magnesium levels in the range 1.5 – 2.5 mmol/L cause vasodilatation in the peripheral and coronary circulation and corresponding increases of 20 – 25% in cardiac output and coronary blood flow. There is little change in heart rate or blood pressure. Animal studies suggest that the effect of magnesium ions on cardiac muscle is to slow the rate of the sinoatrial node impulse formation and prolong conduction time. Limited data on patients with no evidence of heart disease indicate that intravenous magnesium prolongs PR interval, H (atria-His bundle) interval, antegrade AV nodal effective refractory period and sinoatrial conduction time. Within this concentration range there are no detectable effects on CNS function or neuromuscular transmission.
When given intravenously, magnesium sulfate has an immediate onset of action and its duration of activity is about 30 minutes. The onset of action of intramuscular magnesium sulfate is about one hour and its duration of action 3 – 4 hours.
5.2 Pharmacokinetic properties
The amount of elemental magnesium provided by each g of magnesium sulfate heptahydrate is 4.1 mmol.
Distribution
Infused magnesium is distributed rapidly throughout the entire extracellular fluid space and some is taken up by bone but none by red blood cells.
About 40% of plasma magnesium is protein bound and is not ultrafiltrable. Most of the plasma Mg is bound with albumin, globulin and proteins and therefore not filterable at the glomerulus. The injected magnesium sulfate is promptly bound to plasma proteins to the same degree as that of endogenous magnesium.
Biotransformation
Magnesium sulfate is not metabolized.
Elimination
The major excretory pathway is renal and parenteral loads are rapidly eliminated in this way. Faecal loss is very limited.
Renal impairment
In renal impairment, there may be accumulation of magnesium.
5.3 Preclinical safety data
5.3 Preclinical safety dataThere are no preclinical data of relevance to the prescriber additional to those already included in other sections of the SPC.
6.1 List of excipients
Water for injections
Sulfuric acid (for pH adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products/diluents except Glucose 5% or sodium chloride 0.9%.
Magnesium sulfate is incompatible with alkali hydroxides (forming insoluble magnesium hydroxide), alkali carbonates (forming insoluble magnesium carbonate) and salicylates. The activities of streptomycin sulfate and tetramycin sulfate are inhibited by magnesium ions.
6.3
Shelf life 36 months
From a 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 responsibilities of the user.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Polypropylene ampoules of 10 mL containing a 10% w/v solution of magnesium sulfate as heptahydrate for injection/infusion. Packed in cartons to contain 10, 20 or 50 ampoules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalFor intramuscular use, a 50% w/v solution should be used.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
DEMO S.A. PHARMACEUTICAL INDUSTRY
21st Km National Road Athens-Lamia
14568 Krioneri, Attiki, Greece,
T: 210 8161802, F: 210 8161587
8 MARKETING AUTHORISATION NUMBER(S)
PL 17589/0010
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
23/08/2017