Neomansonil may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Praziquantel is reported as an ingredient of Neomansonil in the following countries:
International Drug Name Search
Puri-Nethol® 50 mg tablets
Each tablet contains 50 mg of 6-mercaptopurine.
For a full list of excipients, see section 6.1.
Tablets
Pale yellow, round tablets, biconvex, scored on one side, engraved GX above the score and EX2 below the score and plain on the other side
Cytotoxic agent.
Puri-Nethol is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and it is particularly indicated for maintenance therapy in: acute lymphoblastic leukaemia; acute myelogenous leukaemia. Puri-Nethol may be used in the treatment of chronic granulocytic leukaemia.
For oral administration
Dosage in adults and children:
For adults and children the usual starting dose is 2.5 mg/kg bodyweight per day, or 50-75 mg/m2 body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with Puri-Nethol.
The dosage should be carefully adjusted to suit the individual patient.
Puri-Nethol has been used in various combination therapy schedules for acute leukaemia and the literature should be consulted for details.
Dosage in the elderly:
No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the Puri-Nethol dosage.
Dosage in renal impairment:
Consideration should be given to reducing the dosage in patients with impaired renal function.
Dosage in hepatic function:
Consideration should be given to reducing the dosage in patients with impaired hepatic function.
In general:
When Zyloric (allopurinol) and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given since Zyloric (allopurinol) decreases the rate of catabolism of 6-mercaptopurine.
Hypersensitivity to any component of the preparation.
In view of the seriousness of the indications there are no other absolute contra-indications.
Puri-Nethol is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Safe handling of Puri-Nethol Tablets:
See section 6.6 Instructions for Use/Handling
Monitoring:
Treatment with Puri-Nethol causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy.
The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately.
Bone marrow suppression is reversible if Puri-Nethol is withdrawn early enough.
During remission induction in acute myelogenous leukaemia the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppresive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with Puri-Nethol. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in combination with other cytotoxics (see Section 4.8 Undesirable Effects). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.
Puri-Nethol is hepatotoxic and liver function tests should be monitored weekly during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue Puri-Nethol immediately if jaundice becomes apparent.
During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy.
Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.
The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
Mutagenicity and carcinogenicity:
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4 – 1.0 mg/kg/day.
In view of its action on cellular deoxyribonucleic acid (DNA) 6-mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenisis with this treatment.
Two cases have been documented of the occurrence of acute nonlymphatic leukaemia in patients who received 6-mercaptopurine, in combination with other drugs, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine and later developed acute nonlymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine played a causative role.
A patient with Hodgkins Disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine is used (an unlicensed indication) in combination with anti-TNF agents (see section 4.8 Undesirable Effects).
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
When Zyloric (allopurinol) and Puri-Nethol are administered concomitantly it is essential that only a quarter of the usual dose of Puri-Nethol is given since Zyloric decreases the rate of catabolism of Puri-Nethol.
Inhibition of the anticoagulant effect of warfarin, when given with Puri-Nethol, has been reported.
As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Puri-Nethol therapy (see Section 4.4 Special Warnings and Precautions for Use).
Pregnancy:
6-mercaptopurine is potentially teratogenic. The use of Puri-Nethol should be avoided whenever possible during pregnancy. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving Puri-Nethol tablets.
Maternal Exposure:
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical Safety Data). The potential risk for humans is unclear.
Normal offspring have been born after mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy. Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.
Paternal Exposure:
Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine.
Effects on fertility:
The effect of Puri-Nethol therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence. Transient profound oligospermia was observed in a young man who received 6-mercaptopurine 150 mg/day plus prednisone 80 mg/day for acute leukaemia. Two years after cessation of the chemotherapy, he had a normal sperm count and he fathered a normal child.
Lactation:
6-Mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine and thus mothers receiving Puri-Nethol should not breast-feed.
There are no data on the effect of 6-mercaptopurine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects.
The following convention has been utilised for the classification of undesirable effects:- Very common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very Rare: secondary leukaemia and myelodysplasia (see Section 4.4 Special Warnings and Precautions for Use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see Section 4.4 Special Warnings and Precautions for Use).
Blood and lymphatic system disorders | |
Very common | Bone marrow suppression; leucopenia and thrombocytopenia. |
The main side effect of treatment with 6-mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia. | |
Uncommon | anaemia |
Immune system disorders | |
Hypersensitivity reactions with the following manifestations have been reported: | |
Rare: | Arthralgia; skin rash; drug fever |
Very Rare: | Facial oedema |
Metabolism and nutrition disorders | |
Uncommon | Anorexia |
Gastrointestinal disorders | |
Common | Nausea; vomiting; pancreatitis in the IBD population* (an unlicensed indication) |
Rare | Oral ulceration; pancreatitis (in the licensed indications) |
Very rare | Intestinal ulceration |
Hepato-biliary disorders | |
Common | Biliary stasis; hepatotoxicity |
Rare | Hepatic necrosis |
6-mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary stasis
The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended dose of 2.5 mg/kg bodyweight daily or 75 mg/m2 body surface area per day is exceeded.
Monitoring of liver function tests may allow early detection of hepatotoxicity. This is usually reversible if 6-mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred.
Skin and subcutaneous tissue disorders | |
Rare | alopecia |
Reproductive system and breast disorders | |
Very Rare | Transient oligospermia |
Symptoms and signs:
Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Puri-Nethol. Liver dysfunction and gastroenteritis may also occur.
The risk of overdosage is also increased when Zyloric is being given concomitantly with Puri-Nethol (see Section 4.5 Interactions with other Medicaments and other forms of Interaction).
Management:
As there is no known antidote the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.
Further management should be as clinically indicated or as recommended by the national poisons centre.
ATC Code: L01BB02
Pharmacotherapeutic group:
6-Mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite.
Mode of Action:
6-Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to tioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The tioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.
The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism (when administered orally at a dosage of 75 mg/m2 to 7 paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%).
The elimination half-life of 6-mercaptopurine is 90 ± 30 minutes, but the active metabolites have a longer half-life (approximately 5 hours) than the parent drug. The apparent body clearance is 4832 ± 2562 ml/min/m2. There is low entry of 6-mercaptopurine into the cerebrospinal fluid.
The main method of elimination for 6-mercaptopurine is by metabolic alteration. The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase is the main catabolic enzyme of 6-mercaptopurine and it converts the drug into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.
6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and chromosome damage has been reported in mice, rats and man.
Teratogenicity
6-Mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat, hamster and rabbit at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and the type of malformations are dependent on the dose and stage of the gestation at the time of administration.
Lactose
Maize Starch
Hydrolysed Starch
Stearic Acid
Magnesium Stearate
Purified Water
None known
60 months
Store below 25ÂșC. Keep the bottle tightly closed.
Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.
Pack size: 25 tablets
Safe handling and disposal:
It is recommended that 6-mercaptopurine tablets should be handled following the prevailing local recommendations and/or regulations for the handling and disposal of cytotoxic drugs.
ALKOPHARMA SARL
45-47, rte d'Arlon
L – 1140 Luxembourg
PL 36637/0006
29 August 2006
September 2010
POM
Aciclovir Solka may be available in the countries listed below.
Aciclovir is reported as an ingredient of Aciclovir Solka in the following countries:
International Drug Name Search
Zirtek Allergy Solution 1mg/ml oral solution.
One ml of solution contains 1 mg cetirizine dihydrochloride
Excipients
- One ml of solution contains 450 mg sorbitol (solution at 70%, non crystallizing)
- One ml of solution contains 1.35 mg methylparahydroxybenzoate
- One ml of solution contains 0.15 mg propylparahydroxybenzoate
For full list of excipients, see section 6.1
Oral solution
Clear and colourless liquid
In adults and children 2 years and above
- Cetirizine is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis
- Cetirizine is indicated for the relief of symptoms of chronic idiopathic urticaria.
Children aged from 2 to 6 years: 2.5 mg twice daily (2.5 ml oral solution twice daily (a half spoon twice daily)).
Children aged from 6 to 12 years: 5 mg twice daily (5 ml oral solution bid (a full spoon twice daily).
Adults and adolescents over 12 years of age: 10 mg once daily (10 ml oral solution (2 full spoons)).
The solution can be swallowed as such.
Elderly subjects: data do not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal.
Patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairment. Since cetirizine is mainly eliminated via renal route (see section 5.2), in cases no alternative treatment can be used, the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:
Dosing adjustments for adult patients with impaired renal function
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In pediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, his age and his body weight.
Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.
Patients with hepatic impairment and renal impairment: dose adjustment is recommended (see Patients with moderate to severe renal impairment above).
Hypersensitivity to the active substance, to any of the excipients, to hydroxyzine or to any piperazine derivatives.
Patients with severe renal impairment at less than 10 ml/min creatinine clearance.
Patients with rare hereditary problems of fructose intolerance should not take cetirizine 1 mg/ml oral solution.
At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.
Caution in epileptic patients and patients at risk of convulsions is recommended.
The use of the product is not recommended in children aged less than 2 years.
Methylparahydroxybenzoate and propylparahydroxybenzoate may cause allergic reactions (possibly delayed).
Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).
The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.
For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant or breast feeding women because cetirizine passes into breast milk.
Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10 mg.
Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.
Although cetirizine is a selective antagonist of peripheral H1-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.
Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine dihydrochloride.
Clinical trials
Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.
From this pooling, the following adverse events were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0 % or greater:
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Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.
Adverse drug reactions at rates of 1 % or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacoclinical trials are:
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Post-marketing experience
In addition to the adverse effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in post-marketing experience. For these less frequently reported undesirable effects, the estimated frequencies (uncommon:
Blood and lymphatic disorders : Very rare: thrombocytopenia.
Immune system disorders : Rare: hypersensitivity; Very rare: anaphylactic shock
Psychiatric disorders : uncommon : agitation ; rare : aggression, confusion, depression, hallucination, insomnia, very rare : tic
Nervous system disorders : Uncommon: paraesthesia; Rare: convulsions, movement disorders; Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia
Eye disorders : Very rare: accommodation disorder, blurred vision, oculogyration
Cardiac disorders : Rare: tachycardia
Gastro-intestinal disorders : Uncommon: diarrhoea
Hepatobiliary disorders : Rare: abnormal hepatic function (increased transaminases, alkaline, phosphatase, Îł-GT and bilirubin)
Skin and subcutaneous tissue disorders :Uncommon: pruritus, rash, Rare: urticaria, Very rare: angioneurotic oedema, fixed drug eruption
Renal and urinary disorders : Very rare: dysuria, enuresis
General disorders and administration site conditions: Uncommon: asthenia, malaise; Rare: oedema
Investigations : Rare: weight increase.
a) Symptoms
Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.
Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.
b) Management
There is no known specific antidote to cetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.
Cetirizine is not effectively removed by dialysis.
Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07
Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H1-receptors. In vitro receptor binding studies have shown no measurable affinity for other than H1-receptors.
In addition to its anti-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.
Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.
In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.
In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.
In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of QT interval.
At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.
The steady – state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC), is unimodal in human volunteers.
The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.
The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3 %. Cetirizine does not modify the protein binding of warfarin.
Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.
Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.
Special populations
Elderly: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40 % in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.
Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours.
Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70 % decrease in clearance compared to healthy volunteers.
Patients on hemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70 % decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2).
Hepatically impaired patients: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50 % increase in half-life along with a 40 % decrease in clearance compared to healthy subjects.
Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
- Sorbitol solution at 70 % (non crystallizing) (E420)
- Glycerol
- Propylene glycol
- Sodium saccharinate
- Methylparahydroxybenzoate (E 218)
- Propylparahydroxybenzoate (E 216)
- Banana flavor 54.330/A (Firmenich)
- Sodium acetate
- Glacial acetic acid
- Purified water
Not applicable
5 years.
This medicinal product does not require any special storage conditions.
Amber glass bottle (type III) of 60, 75, 100, 125, 150, or 200 ml, closed with a white polypropylene child-resistant closure.
A 5ml Dosing spoon with a line at 2.5 ml is provided with the bottle.
Not all pack sizes may be marketed.
No special requirements
UCB Pharma Limited,
208 Bath Road
Slough
Berkshire
SL1 3WE
PL 00039/0540
12 December 2005
01 July 2010
ZYPADHERA*
Each 210 mg vial contains olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. After reconstitution each ml of suspension contains 150 mg olanzapine.
Each 300 mg vial contains olanzapine pamoate monohydrate equivalent to 300 mg olanzapine. After reconstitution each ml of suspension contains 150 mg olanzapine.
Each 405 mg vial contains olanzapine pamoate monohydrate equivalent to 405 mg olanzapine. After reconstitution each ml of suspension contains 150 mg olanzapine.
For a full list of excipients see section 6.1.
Powder and solvent for prolonged release suspension for injection.
Powder: yellow solid
Solvent: clear, colourless to slightly yellow solution.
Maintenance treatment of adult patients with schizophrenia sufficiently stabilised during acute treatment with oral olanzapine.
FOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY. (See section 4.4.)
ZYPADHERA should only be administered by deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique and in locations where post-injection observation and access to appropriate medical care in the case of overdose can be assured.
After each injection, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose. It should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved (see section 4.4).
Patients should be treated initially with oral olanzapine before administering ZYPADHERA, to establish tolerability and response.
For Instructions for Use, see section 6.6.
Do not confuse ZYPADHERA 210 mg, 300 mg, and 405 mg, powder and solvent for prolonged release suspension for injection with olanzapine 10 mg powder for solution for injection.
In order to identify the first ZYPADHERA dose for all patients, the scheme in Table 1 should be considered.
Table 1. Recommended dose scheme between oral olanzapine and ZYPADHERA
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Dose adjustment
Patients should be monitored carefully for signs of relapse during the first one to two months of treatment. During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period. During treatment, dose may subsequently be adjusted on the basis of individual clinical status. After clinical reassessment, dose may be adjusted within the range 150 mg to 300 mg every 2 weeks or 300 to 405 mg every 4 weeks. (Table 1.)
Supplementation
Supplementation with oral olanzapine was not authorised in double-blind clinical studies. If oral olanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from both formulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day.
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from ZYPADHERA to other antipsychotic medicinal products. Due to the slow dissolution of the olanzapine pamoate salt which provides a slow continuous release of olanzapine that is complete approximately six to eight months after the last injection, supervision by a clinician, especially during the first 2 months after discontinuation of ZYPADHERA, is needed when switching to another antipsychotic product, and is considered medically appropriate.
Elderly patients
ZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA is not recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not routinely indicated, but should be considered for those 65 and over when clinical factors warrant. ZYPADHERA is not recommended to be started in patients >75 years (see section 4.4).
Patients with renal and/or hepatic impairment
Unless a well-tolerated and effective dose regimen using oral olanzapine has been established in such patients, ZYPADHERA should not be used. A lower starting dose (150 mg every 4 weeks) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 150 mg every 4 weeks and only increased with caution.
Gender
The starting dose and dose range need not be routinely altered for female patients relative to male patients.
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the dose. When indicated, dose escalation should be performed with caution in these patients.
Paediatric population
ZYPADHERA is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Hypersensitivity to the active substance or to any of the excipients.
Patients with known risk of narrow-angle glaucoma.
Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular or subcutaneous injection (see section 6.6).
Use in patients who are in an acutely agitated or severely psychotic state
ZYPADHERA should not be used to treat patients with schizophrenia who are in an acutely agitated or severely psychotic state such that immediate symptom control is warranted.
Post-injection syndrome
During pre-marketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose were reported in patients following an injection of ZYPADHERA. These reactions occurred in <0.1% of injections and approximately 2% of patients. Most of these patients have developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion. In most cases, initial signs and symptoms related to this reaction have appeared within 1 hour following injection, and in all cases full recovery was reported to have occurred within 24 - 72 hours after injection. Reactions occurred rarely (<1 in 1,000 injections) between 1 and 3 hours, and very rarely (<1 in 10,000 injections) after 3 hours. Patients should be advised about this potential risk and the need to be observed for 3 hours in a healthcare facility each time ZYPADHERA is administered.
Prior to giving the injection, the healthcare professional should determine that the patient will not travel alone to their destination. After each injection, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.
It should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved.
For the remainder of the day after injection, patients should be advised to be vigilant for signs and symptoms of overdose secondary to post-injection adverse reactions, be able to obtain assistance if needed, and should not drive or operate machinery (see section 4.7).
If parenteral benzodiazepines are essential for management of post-injection adverse reactions, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended (see section 4.5).
Injection site-related adverse events
The most commonly reported injection site-related adverse reaction was pain. The majority of these reactions were reported to be of “mild” to “moderate” severity. In the event of an injection site-related adverse reaction occurring, appropriate measures to manage these events should be taken (see section 4.8).
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in oral olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in oral olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse reactions (CVAE's e.g., stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with oral olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All oral olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.
Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and oral olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Oral olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with oral olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Hyperglycaemia and diabetes
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g., measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including ZYPADHERA, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g., at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders. Patients treated with any antipsychotic agents, including ZYPADHERA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g., at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported very rarely (<0.01%) when oral olanzapine is stopped abruptly.
QT interval
In clinical trials with oral olanzapine, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]
Thromboembolism
Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (
General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.
Tardive dyskinesia
In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.
Sudden cardiac death
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.
Paediatric population
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).
Use in elderly patients (>75 years)
No information on the use of ZYPADHERA in patients >75 years is available. Due to biochemical and physiological modification and reduction of muscular mass, this formulation is not recommended to be started in this sub-group of patients.
Paediatric population
Interaction studies have only been performed in adults.
Caution should be exercised in patients who receive medicinal products that can induce hypotension or sedation.
Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female non-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). Thus, no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.
General CNS activity
Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).
QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast feeding
In a study of oral olanzapine in breast feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine.
No studies on the effects on the ability to drive and use machines have been performed. As olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.
Patients should be advised not to drive or operate machinery for the remainder of the day after each injection due to the possibility of a post-injection syndrome event leading to symptoms consistent with olanzapine overdose (see section 4.4).
Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistent with olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion.
Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen with oral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statistically significantly higher rate in the ZYPADHERA group than in the placebo group was sedation (ZYPADHERA 8.2%, placebo 2.0%). Among all ZYPADHERA-treated patients, sedation was reported by 4.7% of patients.
In clinical trials with ZYPADHERA, the incidence of injection site-related adverse reactions was approximately 8%. The most commonly reported injection site-related adverse reaction was pain (5%); some other injection site-adverse reactions reported were (in decreasing frequency): nodule-type reactions, erythema-type reactions, non-specific injection-site reactions, irritation, oedema-type reactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% of patients.
The undesirable effects listed below have been observed following administration of oral olanzapine but may occur following administration of ZYPADHERA.
Adults
The most frequently (seen in
The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (
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1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short-term treatment (median duration 47 days), weight gain
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.
3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (
4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (
5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (
6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine-treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. Generally, in olanzapine-treated patients potentially associated breast- and menstrual-related clinical manifestations (e.g., amenorrhoea, breast enlargement, galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g., erectile dysfunction in males and decreased libido in both genders) were commonly observed.
Long-term exposure (at least 48 weeks)
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
Additional information on special populations
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (
Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.
The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (
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9 Following short-term treatment (median duration 22 days), weight gain
10 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (
11 Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (
12 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
If signs and symptoms of overdose consistent with post-injection syndrome are observed, appropriate supportive measures should be taken (see section 4.4).
While overdose is less likely with parenteral than oral medicinal products, reference information for oral olanzapine overdose is presented below:
Signs and symptoms
Very common symptoms in overdose (>10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (< 2% of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute oral overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.
Management of overdose
There is no specific antidote for olanzapine. Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
