- OTSUMOL Infusion

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آٹسومول  انفیوژن (پیراسیٹامول    ١۰ ملی گرام / ملی لیٹر)

OTSUMOL Infusion
(Paracetamol 10mg/ml)
 
Therapeutic Class
Anti-pyretic, Analgesic. Paracetamol is also known as acetaminophen

Description
OTSUMOL (paracetamol) solution for infusion is a clear and slightly yellowish solution. It contains 10mg/mL of paracetamol. Paracetamol is a white crystalline solid or powder. It is soluble in water (1 in 70), soluble in alcohol (1 in 7), acetone (1 in 13), glycerol (1 in 40), propylene glycol (1 in 9) and also soluble in solutions of the alkali hydroxides.
OTSUMOL solution for infusion contains 10mg/mL of paracetamol (100mL infusion contains 1000mg or 1gm of paracetamol)

Pharmacology 
 
PHARMACODYNAMICS
The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.
Paracetamol 10mg/mL, solution for infusion provides onset of pain relief within 5 to 10 minutes after the start of administration. The peak analgesic effect is obtained in 1 hour and the duration of this effect is usually 4 to 6 hours.
Paracetamol 10mg/mL, solution for infusion reduces fever within 30 minutes after the start of administration with duration of the antipyretic effect of at least 6 hours.

PHARMACOKINETICS
Adults
Absorption:
Paracetamol pharmacokinetics is linear after a single administration of up to 2 g and after repeated administration during 24 hours.
The bioavailability of paracetamol following infusion of 1 g of Paracetamol 10mg/mL is similar to that observed following infusion of 2 g propacetamol (containing 1 g paracetamol). Peak plasma concentration is obtained as and from the end of infusion. The maximum plasma concentration (Cmax) of paracetamol observed following intravenous infusion of 1 g Paracetamol 10 mg/mL is about 30μg/mL. About 15 minutes is required to obtain the maximal plasma concentration (T max).

Distribution:
The volume of distribution of paracetamol is approximately 1 L/kg.
Paracetamol is not extensively bound to plasma proteins.
Following infusion of 1g propacetamol, significant concentrations of paracetamol (about 1.5μg/mL) were observed in the cerebrospinal fluid 20 minutes after infusion.

Metabolism:
Paracetamol is metabolized mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulphuric acid conjugation. The latter route is rapidly saturable at doses that exceed the therapeutic doses. A small fraction (less than 4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, during massive poisoning, the quantity of this toxic metabolite is increased.
At therapeutic doses, CYP3A4, the major isoform of P450 in human liver, contributes to the production of the cytotoxic metabolite. For very high, supratherapeutic plasma concentrations (1500 mg/ L) of paracetamol, the 2E1 and 1A2 isoforms may also be involved.

Elimination:
The metabolites of paracetamol are mainly excreted in the urine. 90% of the dose administered is excreted in 24 hours, mainly as glucuronide (60-80%) and sulphate (20-30%) conjugates. Less than 5% is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is
18 L/h.
 
Neonates and Infants <6 months of age
Examining the pharmacokinetics of Paracetamol in neonates and infants <6 months of age are limited. The safety and efficacy of Paracetamol in premature neonates has not been established
 
In neonates, the plasma half-life is longer than in infant’s i.e. around 3.5 hours. Neonates and, infants excrete significantly less glucuronide and more sulphate conjugates than adults. The potential effect of immaturity in metabolic and elimination pathways of paracetamol should be considered when administering paracetamol to neonates and children <6 months of age.
Infants and children >6 months of age
The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those observed in adults, except for the plasma half-life that is slightly shorter (1.5 to 2 h) than in adults
 
Special populations
Renal Impairment
Paracetamol should be administered with caution to patients with renal impairment. In cases of severe renal impairment (creatinine clearance ≤ 30 mL/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times slower in subjects with severe renal impairment than in healthy subjects. It is recommended that there be an interval of at least 6 hours between administrations in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min).

Hepatic Impairment
Paracetamol should be administered with caution to patients with hepatic impairment. Hepatic impairment may decrease the clearance of paracetamol or increase the probability of hepatic toxicity.
 
Elderly subjects
There was a significant increase in AUC and reduction in clearance of paracetamol and its metabolites in elderly subjects. However, these statistically significant differences were not likely to be clinically relevant during short-term infusions. Hence, no dose adjustment is required in this population.
 
Indications
 
OTSUMOL 10 mg/mL, solution for infusion is indicated for the relief of mild to moderate pain and the reduction of fever where an intravenous route of administration is considered clinically necessary.
 
It would be particularly helpful to those patients who are unable to take oral medicines due to impaired GI motility or those who require faster relief from fever and pain.

Otsumol would also be a quality addition to the concept of multimodal analgesia that is being proposed and is recommended whenever possible.
 
Dosage & Administration:
 
The prescribed dose must be based on the patient’s weight.
 
Unintentional overdose can lead to serious liver damage and death. Healthcare providers are reminded that it is essential to follow both the weight-related dose recommendations and to consider individual patient risk factors for hepatotoxicity including hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration.
It is recommended that a suitable oral analgesic treatment be substituted for OTSUMOL as soon as the patient can be treated by oral route.

Intravenous route:
OTSUMOL 10 mg/mL, solution for infusion should not be mixed with other medicinal products.
  
Dosage:
Dosing is based on patient weight. Dosing recommendations are presented in the table below:
 

Patient Weight	Paracetamol dose (10 mg/mL) per administration	Minimum interval between each administration	Maximum daily dose #
> 50 kg	1 g (i.e. one 100 mL infusion) Up to 4 times per day	4 hours*	≤ 4 g Must not exceed 4 g in 24 hours.
> 33 kg and ≤ 50 kg	15 mg/kg (i.e. 1.5 mL solution per kg) Up to 4 times per day	4 hours*	≤ 60 mg/kg, without exceeding 3 g Must not exceed 3 g in 24 hours.
> 10 kg and ≤ 33 kg	15 mg/kg (i.e. 1.5 mL solution per kg) Up to 4 times per day	6 hours	≤ 60 mg/kg, without exceeding 2 g Must not exceed 2 g in 24 hours.
≤ 10 kg**	7.5 mg/kg (i.e. 0.75 mL solution per kg) The volume must not exceed 7.5 mL per dose. Up to 4 times per day	6 hours	≤ 30 mg/kg Must not exceed 30 mg/kg in 24 hours.

* The minimum interval between each administration must be 4 hours in patients without hepatic or renal impairment. However, in patients with renal and/or hepatic impairment the minimum interval between doses must not be less than 6 hours.
# the maximum daily dose takes into account all medicines containing paracetamol or propacetamol.
** No safety and efficacy data are available for premature neonates. There is limited data on the use of OTSUMOL in neonates and infants <6 months of age
 
Hepatic Impairment
In patients with impaired hepatic function, the dose must be reduced or the dosing interval prolonged. The maximum daily dose should not exceed 60 mg/kg/day (not exceeding 2 g/day) in the following situations:

• Adults weighing less than 50 kg
• Chronic or compensated active hepatic disease, especially those with mild to moderate hepatocellular insufficiency
• Gilbert’s syndrome (familial hyperbilirubinaemia)
• Chronic alcoholism
• Chronic malnutrition (low reserves of hepatic glutathione)
• Dehydration

Method of administration
The paracetamol solution is administered as a 15-minute intravenous infusion; it contains no antimicrobial agent, and is for single use in one patient only.
OTSUMOL 10mg/mL solution for infusion can also be diluted in a 0.9% Sodium Chloride or 5% Glucose solution up to one tenth. In this case, use the diluted solution within the hour following its preparation (infusion time included).
As for all solutions for infusion presented in glass infusions, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of the administration route. This monitoring at the end of the perfusion applies particularly for central route infusion, in order to avoid air embolism.
 
It is recommended that for the administration of OTSUMOL 10mg/mL solution for infusion a syringe or giving set with a diameter equal to or below 0.8mm should be used for solution sampling. In addition, it is recommended that the bung is pierced at the location specifically designed for needle introduction (where the thickness of the bung is the lowest). If these recommendations are not adhered to the likelihood of bung fragmentation or the bung being forced into the infusion is increased.
Pediatric Patients
OTSUMOL should not be hung as an infusion due to the small volume of the product to be administered in the pediatric population.
To avoid dosing errors in neonates and infants (≤ 10 kg) and confusion between milligrams (mg) and milliliters (mL), it is recommended to specify the intended volume for administration in milliliters (mL). The volume of OTSUMOL (10 mg/mL) administered should never exceed 7.5 mL per dose in this weight group. In neonates and infants (≤ 10 kg), very small volumes will be required. A 5 mL or 10 mL syringe should be used to measure the dose as appropriate for the weight of the child and the desired volume.
For pediatric dosing, the 50 mL infusion of OTSUMOL can be diluted using either a 0.9% sodium chloride solution or a 5% glucose solution up to one-tenth dilution (one volume paracetamol injection into nine volumes diluent). The diluted solution must be used within one hour following its preparation (infusion time included).

Contraindications
 
OTSUMOL 10 mg/mL, solution for infusion is contraindicated in:

• Cases of hypersensitivity to paracetamol or to propacetamol hydrochloride (pro drug of paracetamol) or to any of the excipients,
• Cases of severe hepatocellular insufficiency
• Catients with hepatic failure or decompensated active liver disease

 
It is recommended to use a suitable analgesic oral treatment as soon as this administration route is possible.
In order to avoid the risk of overdose; check that other medicines administered do not contain paracetamol.
 
Doses higher than the recommended entail a risk of very serious liver damage. Clinical symptoms and signs of liver damage are usually seen first after two days with a maximum usually after 4 to 6 days. Treatment with antidote should be given as soon as possible

Precautions
 
OTSUMOL should be used with caution in cases of:
• Hepatocellular insufficiency, including Gilbert’s syndrome (familial hyperbilirubinaemia)
• Severe renal insufficiency (creatinine clearance ≤ 30 mL/min),
• Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency (may lead to haemolytic anaemia),
• Chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks every day),
• Anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione),
• Dehydration, hypovolemia.
 
The total dose of paracetamol should not exceed 4 g per day for patients weighing 50 kg or more, 60 mg/kg for patients weighing 50 kg or less and more than 33 kg (without exceeding 3 g), 60 mg/kg for patients weighing 33 kg or less and more than 10 kg (without exceeding 2 g) and 30 mg/kg for patients weighing 10 kg or less. It is important to consider the contribution of all paracetamol containing medications, including non-prescription, oral or PR forms of the drug to this total daily paracetamol dose prior to administering OTSUMOL. If the daily dose of paracetamol from all sources exceeds the maximum, severe hepatic injury may occur.
 
Paracetamol can cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
 
Hepatic Injury
Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition or dehydration may be at a higher risk of liver damage following administration of OTSUMOL.
 
Effects on Fertility
Intravenous paracetamol (administered as propacetamol) had no effect on fertility of rats at systemic exposure levels (based on AUC) greater than twice those anticipated at the maximum clinical dose.
 
Use in Pregnancy
Pregnancy Category (Category A)
 
Paracetamol has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
 
Nevertheless, OTSUMOL® should only be used during pregnancy after a careful benefit-risk assessment. In pregnant patients, the recommended posology and duration must be strictly observed.
 
Use in Lactation
After oral administration, paracetamol is excreted into breast milk in small quantities. Rash in nursing infants has been reported. However, paracetamol is considered to be compatible with breastfeeding. No signs of toxicity were observed in rat pups of dams that received IV propacetamol postpartum at maternal exposures (based on AUC) greater than twice those anticipated at the maximum clinical dose. OTSUMOL® 10 mg/mL solution for infusion may be used in breast-feeding women, but caution should be observed.
 
INTERACTIONS WITH OTHER MEDICINES
Probenecid causes an almost 2-fold reduction in clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction of the paracetamol dose should be considered for concomitant treatment with probenecid.
 
Caution should be paid to the concomitant intake of enzyme-inducing agents. These substances include but are not limited to: barbiturates, isoniazid, anticoagulants, zidovudine, amoxicillin + clavulanic acid, carbamazepine and ethanol. Induction of metabolism of paracetamol from enzyme inducers may result in an increased level of hepatotoxic metabolites.
 
Concomitant use of paracetamol (4 g per day for at least 4 days) with oral coumarin anticoagulants including warfarin may lead to slight variations of INR values. In this case, increased monitoring of INR values should be conducted during the period of concomitant use as well as for one week after paracetamol treatment has been discontinued.
 
Phenytoin administered concomitantly may result in decreased paracetamol effectiveness and an increased risk of hepatotoxicity. Patients receiving phenytoin therapy should avoid large and/or chronic doses of paracetamol. Patients should be monitored for evidence of hepatotoxicity.
 
Busulfan – busulfan is eliminated from the body via conjugation with glutathione. Concomitant use with paracetamol may result in reduced busulfan clearance.
 
Salicylamide - salicylamide may prolong the elimination half-life (t1/2) of paracetamol.
 
Over dosage
 
There is a risk of poisoning, particularly in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition and in patients receiving enzyme inducers. Poisoning may be fatal in these cases. Acute overdose with paracetamol may also lead to acute renal tubular necrosis.
 
Symptoms generally appear within the first 24 hours and comprise of nausea, vomiting, anorexia, pallor and abdominal pain. Overdose, 7.5 g or more of paracetamol in a single administration in adults or 140 mg/kg of body weight in a single administration in children, causes cytolytic hepatitis likely to induce complete and irreversible hepatic necrosis, resulting in acute or fulminant hepatic failure, hepatocellular insufficiency, metabolic acidosis and encephalopathy, which may lead to coma and death.
 
Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with decreased prothrombin levels that may appear 12 to 48 hours after administration. Clinical symptoms of liver damage are usually evident initially after two days, and reach a maximum after 4 to 6 days.
The Rummack-Matthews nomogram relates plasma levels of paracetamol and the time after oral ingestion to the predicted severity of liver injury. The relation of parental paracetamol levels in overdose to liver toxicity has not been examined. Advice or treatment protocols based on oral paracetamol overdoses may not accurately predict the incidence of liver toxicity or need for antidote therapy in OTSUMOL overdose.
 
Emergency measures

• Immediate hospitalization
• Treatment of paracetamol overdose may include the antidote N-acetyl cysteine (NAC) by the IV or oral route. In overdoses of oral paracetamol NAC is administered, if possible, before 8 hours but may give some degree of protection from liver toxicity even after this time. The optimal time for administration of NAC and necessary duration of therapy have not been established for overdoses of OTSUMOL
• Take blood for plasma paracetamol assay, as soon as possible after the overdose
• Symptomatic treatment
• Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases hepatic transaminases return to normal in one to two weeks with full restitution of the liver function. In very severe cases, however, liver transplantation may be necessary

 
Adverse Effects
 
The overall incidence of adverse events in OTSUMOL-treated patients compared to placebo within the clinical trial set; can be observed in the tables below.
 
Adverse Events in Adults - greater than 1% (observed in the clinical trial set)
 

	OTSUMOL % n = 99	Placebo % n = 102
Neurological Dizziness Headache Dystonia	2.7 1.3	2.9 4.9
Gastrointestinal Vomiting Dry mouth Diarrhea Constipation Nausea Dyspepsia Enlarged abdomen Gastrointestinal disorder NOS	4.0   1.3 6.7 10.0 1.3 2.0 2.0	2.9     11.8 8.8
Haematological Anemia Post-operative hemorrhage	2.7 2.0	6.9
Hepatobiliary Gamma GT – increase SGPT – increase	1.3 1.3
Psychiatric Insomnia		1.96
Skin and Appendage Injection site pain Injection site reaction Post-operative site reaction Pruritus	2.0 2.67 2.67 3.3	4.9
Respiratory Alveolitis Coughing	1.3 2.0	2.94
Endocrine/Metabolic Hyperglycemia Hypokalaemia	1.3 1.3
General Fatigue Fever Oedema – peripheral Chest pain	1.59     1.33	5.9

 
 
Adverse Events in Children - greater than 1% (observed in the clinical trial set)
 

	OTSUMOL % n = 95
Skin and Appendage Injection site pain Injection site reaction	14.74
Neurological Hypotonia	1.05
Gastrointestinal Nausea Vomiting Abdominal pain Eructation	1.05 5.26
Body As A Whole Fever	1.05

As with all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000), they are described below:
 

Organ System	Rare >1/10000, <1/1000	Very rare <1/10000	Isolated reports
General disorders and administration site condition	Malaise	Hypersensitivity reaction
Cardiac disorders	Hypotension	Shock
Hepatobiliary disorders	Increased levels of hepatic transaminases
Blood and the lymphatic system disorders	Agranulocytosis, neutropenia		Thrombocytopenia
Neurological		Neurological disorders	Coma
Renal/Genitourinary		Acute renal failure
Skin and subcutaneous tissue disorders	Macular rash, injection site reaction	Maculo-papular rash, pemphigoid reaction, pustular rash	Lyell Syndrome

 
Post Market Adverse Effects for Propacetamol/Paracetamol
The following adverse events have also been reported during postmarketing surveillance, but the incidence rate (frequency) is not known.
 

Organ System	Adverse Event
Blood and the lymphatic system disorders	- Thrombocytopenia
Cardiac disorders	- Tachycardia
Gastrointestinal disorders	- Nausea - Vomiting
General disorders and administration site conditions	- Administration site reaction
Hepatobiliary disorders	- Fulminant hepatitis - Hepatic necrosis - Hepatic failure - Hepatic enzymes increased
Immune system disorders	- Angioneurotic (Quincke’s) edema - Anaphylactic shock - Anaphylaxis - Hypersensitivity reactions (ranging from simple skin rash or urticaria to anaphylactic shock) have been reported and require the discontinuation of treatment
Skin and subcutaneous tissue disorders	- Erythema - Flushing - Pruritus - Rash - Urticaria                     - Acute generalised exanthematous pustulosis - Toxic epidermal necrolysis - Stevens-Johnson syndrome

 
Pharmaceutical Precautions
One 100 mL infusion contains 1000mg or 1gm of paracetamol.
The solution is clear to slightly yellowish.
Store below 25°C.
Do not refrigerate or freeze.
Before administration, the product should be visually inspected for any particulate matter and discoloration.
For single use only.
The product should be used immediately after opening and any unused solution should be discarded.
If diluted in 0.9% Sodium Chloride or 5% Glucose, the solution should be used immediately. However, if the solution is not used immediately, do not store for more than one hour (infusion time included). 
 
Packaging
Paracetamol 10 mg/mL solution for infusion is available in 100mL LLDPE bottle.

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