Losartan Potassium / Hydrochlorothiazide 50 mg / 12.5 mg Film-coated Tablets

1. Name Of The Medicinal Product

Losartan Potassium / Hydrochlorothiazide 50 mg/12.5 mg Film-coated Tablets

2. Qualitative And Quantitative Composition

One film-coated tablet contains 50 mg losartan potassium and 12.5 mg hydrochlorothiazide.

One film-coated tablet contains 26.9 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Light yellow, round, biconvex film-coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Losartan Potassium / Hydrochlorothiazide is indicated for the treatment of essential hypertension in patients whose blood pressure is not adequately controlled on losartan or hydrochlorothiazide alone.

4.2 Posology And Method Of Administration

Losartan Potassium / Hydrochlorothiazide may be administered with other antihypertensive agents.

Losartan Potassium / Hydrochlorothiazide tablets should be swallowed with a glass of water.

Losartan Potassium / Hydrochlorothiazide may be administered with or without food.

Hypertension

Losartan and hydrochlorothiazide is not for use as initial therapy, but in patients whose blood pressure is not adequately controlled by losartan potassium or hydrochlorothiazide alone.

Dose titration with the individual components (losartan and hydrochlorothiazide) is recommended.

When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled.

The usual maintenance dose is one tablet of Losartan Potassium / Hydrochlorothiazide 50 mg/12.5 mg Film-coated Tablets (losartan 50 mg/HCTZ 12.5 mg) once daily. For patients who do not respond adequately to Losartan Potassium / Hydrochlorothiazide 50 mg/12.5 mg Film-coated Tablets, the dosage may be increased to maximum 2 tablets daily of Losartan Potassium / Hydrochlorothiazide 50 mg/12.5 mg Film-coated Tablets or one tablet of Losartan Potassium / Hydrochlorothiazide 100 mg/25 mg Film-coated Tablets (losartan 100 mg/ HCTZ 25 mg) once daily. In general, the antihypertensive effect is attained within three to four weeks after initiation of therapy.

Use in patients with renal impairment and haemodialysis patients

No initial dosage adjustment is necessary in patients with moderate renal impairment (i.e. creatinine clearance 30-50 ml/min). Losartan and hydrochlorothiazide tablets are not recommended for haemodialysis patients. Losartan/HCTZ tablets must not be used in patients with severe renal impairment (i.e. creatinine clearance <30 ml/min) (see section 4.3).

Use in patients with intravascular volume depletion

Volume and /or sodium depletion should be corrected prior to administration of Losartan/HCTZ tablets.

Use in patients with hepatic impairment

Losartan/HCTZ is contraindicated in patients with severe hepatic impairment (see section 4.3.).

Use in the elderly

Dosage adjustment is not usually necessary for the elderly.

Use in children and adolescents (< 18 years)

There is no experience in children and adolescents. Therefore, losartan/hydrochlorothiazide should not be administered to children and adolescents.

4.3 Contraindications

- Hypersensitivity to losartan, sulphonamide-derived substances (as hydrochlorothiazide) or to any of the excipients

- Therapy resistant hypokalaemia or hypercalcaemia

- Severe hepatic impairment; Cholestasis and biliary obstructive disorders

- Refractory hyponatraemia

- Symtomatic hyperuricaemia/gout

- 2nd and 3rd trimester of pregnancy (see section 4.4 and 4.6)

- Lactation (see section 4.6)

- Severe renal impairment (i.e. creatinine clearance <30 ml/min)

- Anuria

4.4 Special Warnings And Precautions For Use

Losartan

Angiooedema

Patients with a history of angiooedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored (see section 4.8).

Hypotension and Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Losartan Potassium / Hydrochlorothiazide tablets (see sections 4.2. and 4.3.).

Electrolyte imbalances

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. Therefore, the plasma concentrations of potassium and creatinine clearance values should be closely monitored; especially patients with heart failure and a creatinine clearance between 30-50 ml/ min should be closely monitored.

The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan/ hydrochlorothiazide is not recommended (see section 4.5).

Liver function impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, Losartan Potassium / Hydrochlorothiazide should be used with caution in patients with a history of mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore Losartan Potassium / Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).

Renal function impairment

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function, including renal failure, have been reported (in particular, in patients whose renal function is dependent on the renin-angiotensin-aldosterone system, such as those with severe cardiac insufficiency or pre-existing renal dysfunction).

As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan Potassium / Hydrochlorothiazide tablets is not recommended.

Coronary heart disease and cerebrovascular disease:

As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyophathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Ethnic differences

As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in nonblacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Pregnancy

Losartan Potassium / Hydrochlorothiazide should not be initiated during pregnancy. Unless continued Losartan/HTCZ therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with Losartan Potassium / Hydrochlorothiazide should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Hydrochlorothiazide

Hypotension and electrolyte/fluid imbalance

As with all antihypertensive therapy, symptomatic hypotension may occur in some patients. Patients should be observed for clinical signs of fluid or electrolyte imbalance, e.g. volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia which may occur during intercurrent diarrhea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients. Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diureticinduced hyperuricemia.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as it may cause intrahepatic cholestasis, and since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Losartan Potassium / Hydrochlorothiazide is contraindicated for patients with severe hepatic impairment (see section 4.3 and 5.2).

Other

In patients receiving thiazides, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Anti-doping test

Hydrochlorothiazide could produce a positive analytical result in an anti-doping test.

Special warnings regarding excipients

Losartan Potassium / Hydrochlorothiazide contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Losartan

Rifampicin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Co-medication is not advisable.

As with other medicines which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be coadministered with angiotensin II receptor antagonists.

When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses) and non-selective NSAIDs, attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

In some patients with compromised renal function who are being treated with non-steroidal antiinflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists may result in a further deterioration of renal function. These effects are usually reversible.

Other substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine: Concomitant use with these drugs that lower blood pressure, as main or side-effect, may increase the risk of hypotension.

Hydrochlorothiazide

When given concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Other antihypertensive drugs:

Additive effect.

Cholestyramine and colestipol resins:

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH:

Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g. adrenaline):

Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g. tubocurarine):

Possible increased responsiveness to the muscle relaxant.

Lithium:

Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol):

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g. atropine, biperiden):

Increase of the bioavailability to thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate):

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates:

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa:

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Ciclosporin:

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Digitalis glycosides:

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

Medicinal products affected by serum potassium disturbances:

Periodic monitoring of serum potassium and ECG is recommended when Losartan/hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

- Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)

- Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

- Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, terfenadine, vincamine IV).

Calcium salts:

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.

Laboratory Test Interactions:

Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see section 4.4).

Carbamazepine:

Risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodine Contrast Media:

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product.

Patients should be rehydrated before the administration.

Amphotericin B (parenteral), corticosteroids, ACTH or stimulant laxatives:

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

4.6 Pregnancy And Lactation

Pregnancy

The use of Losartan Potassium / Hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of Losartan Potassium / Hydrochlorothiazide is contra-indicated during the 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with Losartan Potassium / Hydrochlorothiazide should be stopped immediately and, if appropriate, alternative therapy should be started.

Losartan/hydrochlorothiazide therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also 5.3 'Preclinical safety data').

Should exposure to Losartan Potassium / Hydrochlorothiazide have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken losartan/hydrochlorothiazide should be closely observed for hypotension (see also section 4.3 and 4.4).

Hydrochlorothiazide may reduce both plasma volume and uteroplacental blood flow. Thiazides pass the placental barrier and are found in cord blood. They may cause fetal electrolyte disturbances and possibly other reactions that have been observed in adults. Cases of thrombocytopenia in neonates and fetal or neonatal jaundice were reported after treating the mothers with thiazides.

Lactation

It is not known whether losartan is excreted in human milk. However, losartan is excreted in the milk of lactating rats. Because no information is available regarding the use of losartan during breast-feeding, losartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Thiazides pass into human milk and may inhibit lactation. Because of the potential for adverse effects on the nursing infant, Losartan Potassium / Hydrochlorothiazide is contraindicated during breast-feeding (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

4.8 Undesirable Effects

The adverse events below are classified where appropriate by system organ class and frequency according to the following convention:

Very common:

Common:

Uncommon:

Rare:

Very rare:

Not known:

(cannot be estimated from the available data)

In clinical trials with losartan potassium salt and hydrochlorothiazide, no adverse events peculiar to this combination of substances were observed. The adverse events were restricted to those which were formerly observed with losartan potassium salt and/or hydrochlorothiazide.

In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as substance-related that occurred with an incidence greater than placebo in 1% or more of patients treated with losartan and hydrochlorothiazide.

Next to these effects, there are further adverse reactions reported after the introduction of the product to the market as follows:

Hepato-biliary disorders

Rare: Hepatitis

Investigations

Rare: Hyperkalaemia, elevation of ALT

Additional adverse events that have been seen with one of the individual components and may be potential adverse events with losartan potassium/hydrochlorothiazide are the following:

Losartan

Blood and lymphatic system disorders

Uncommon: Anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis

Immune system disorders

Rare: Anaphylactic reactions, angioedema, urticaria

Metabolism and nutrition disorders

Uncommon: Anorexia, gout

Psychiatric disorders

Common: Insomnia

Uncommon: Anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorder, somnolence, memory impairment

Nervous system disorders

Common: Headache, dizziness

Uncommon: Nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope

Eye disorders

Uncommon: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Cardiac disorders

Uncommon: Hypotension, orthostatic hypotension, sternalgia, angina pectoris, grade II-AV block, cerebrovascular event, myocardial infarction, palpitation, arrhythmias (atrial fibrillations, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation)

Vascular disorders

Uncommon: Vasculitis

Respiratory, thoracic and mediastinal disorders

Common: Cough, upper respiratory infection, nasal congestion, sinusitis, sinus disorder

Uncommon: Pharyngeal discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion

Gastrointestinal disorders

Common: Abdominal pain, nausea, diarrhoea, dyspepsia

Uncommon: Constipation, dental pain, dry mouth, flatulence, gastritis, vomiting

Hepato-biliary disorders

Not known: Liver function abnormalities

Skin and subcutaneous tissue disorders

Uncommon: Alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash, urticaria, sweating

Musculoskeletal and connective tissue disorders

Common: Muscle cramp, back pain, leg pain, myalgia

Uncommon: Arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness

Renal and urinary disorders

Uncommon: Nocturia, urinary frequency, urinary tract infection

Reproductive system and breast disorders

Uncommon: Decreased libido, impotence

General disorders and administration site conditions

Common: Asthenia, fatigue, chest pain

Uncommon: Facial oedema, fever

Investigations

Common: Hyperkalaemia, mild reduction of haematocrit and haemoglobin

Uncommon: Mild increase in urea and creatinine serum levels

Very rare: Increase in hepatic enzymes and bilirubin.

Hydrochlorothiazide

Blood and lymphatic system disorders

Uncommon: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, purpura, thrombocytopenia

Immune system disorders

Rare: Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon: Anorexia, hyperglycaemia, hyperuricaemia, hypokalaemia, hyponatraemia

Psychiatric disorders

Uncommon: Insomnia

Nervous system disorders

Common: Cephalalgia

Eye disorders

Uncommon: Transient blurred vision, xanthopsia

Vascular disorders

Uncommon: Necrotizing angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders

Uncommon: Respiratory distress including pneumonitis and pulmonary oedema

Gastrointestinal disorders

Uncommon: Sialoadenitis, spasms, stomach irritation, nausea, vomiting, diarrhoea, constipation

Hepato-biliary disorders

Uncommon: Icterus (intrahepatic cholestatis), pancreatitis

Skin and subcutaneous tissue disorders

Uncommon: Photosensitivity, urticaria, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Uncommon: Muscle cramps

Renal and urinary disorders

Uncommon: Glycosuria, interstitial nephritis, renal dysfunction, renal failure

General disorders and administration site conditions

Uncommon: Fever, dizziness

4.9 Overdose

No specific information is available on the treatment of overdosage with losartan/hydrochlorothiazide. Treatment is symptomatic and supportive. Therapy with Losartan Potassium / Hydrochlorothiazide should be discontinued and the patient observed closely. Suggested measures include induction of emesis if ingestion is recent, and correction of dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.

Losartan

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor the active metabolite can be removed by hemodialysis.

Hydrochlorothiazide

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combination containing an angiotensin II-receptor(type AT1)-antagonist and a thiazide diuretic, Antihypertensive, ATC code: C09DA01

Losartan-Hydrochlorothiazide

The components of Losartan Potassium / Hydrochlorothiazide have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone. This effect is thought to be a result of the complimentary actions of both components. Further, as a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, decreases serum potassium, and increases the levels of angiotensin II. Administration of losartan blocks all the physiologically relevant actions of angiotensin II and through inhibition of aldosterone could tend to attenuate the potassium loss associated with the diuretic.

Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlorothiazide has been shown to cause modest increases in uric acid; the combination of losartan and hydrochlorothiazide tends to attenuate the diuretic-induced hyperuricemia.

The antihypertensive effect of losartan/hydrochlorothiazde is sustained for a 24-hour period. In clinical studies of at least one year's duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of losartan/hydrochlorothiazide had no clinically significant effect on heart rate. In clinical trials, after 12 weeks of therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg, trough sitting diastolic blood pressure was reduced by an average of up to 13.2 mmHg.

Losartan/hydrochlorothiazide is effective in reducing blood pressure in males and females, blacks and non-blacks and in younger (<65 years) and older (>65 years) patients and is effective in all degrees of hypertension.

Losartan

Losartan is a synthetically produced oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormon of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth-muscle cell proliferation.

Losartan selectively blocks the AT1 receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.

Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is thus no increase in bradykinin-mediated undesirable effects.

During the administration of losartan the removal of the angiotensin II negative feedback on renin secretion leads to increased plasma-renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of the plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After the discontinuation of losartan, PRA and angiotensin II values fell within 3 days to the baseline values.

Both losartan and its principal active metabolite have a far greater affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10- to 40-times more active than losartan on a weight for weight basis.

In a study specifically designed to assess the incidence of cough in patients treated with losartan as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving losartan or hydrochlorothiazide was similar and was significantly less than in patients treated with an ACE inhibitor. In addition, in an overall analysis of 16 double-blind clinical trials in 4131 patients, the incidence of spontaneously reported cough in patients treated with losartan was similar (3.1%) to that of patients treated with placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence with ACE inhibitors was 8.8%.

In nondiabetic hypertensive patients with proteinuria, the administration of losartan potassium significantly reduces proteinuria, fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. Generally losartan causes a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy.

Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.

In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced positive hemodynamic and neurohormonal effects characterized by an increase in cardiac index and decreases in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate and a reduction in circulating levels of aldosterone and norepinephrine, respectively. The occurrence of hypotension was dose related in these heart failure patients.

Hypertension Studies

In controlled clinical studies, once-daily administration of Losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurements of blood pressure 24 hours post-dose relative to 5 – 6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70 – 80 % of the effect seen 5-6 hours postdose.

Discontinuation of Losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, Losartan had no clinically significant effects on heart rate.

Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.

LIFE Study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left ventricular hypertrophy. Patients were randomised to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensives, with the exception of ACE inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.

The mean length of follow up was 4.8 years.

The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95 % confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.

After oral use, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours the antihypertensive effect persists for up to 24 hours.

5.2 Pharmacokinetic Properties

Absorption

Losartan

Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.

Distribution

Losartan

Both losartan and its active metabolite are

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Biotransformation

Losartan

About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.

In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.

Elimination

Losartan

Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During oncedaily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.

Characteristics in Patients

Losartan-Hydrochlorothiazide

The plasma concentrations of losartan and its active metabolite and the absorption of hydrochlorothiazide in elderly hypertensives are not significantly different from those in young hypertensives.

Losartan

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.

Neither losartan nor the active metabolite can be removed by hemodialysis.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, genotoxicity and carcinogenic potential. The toxic potential of the combination of losartan/hydrochlorothiazide was evaluated in chronic toxicity studies for up to six months duration in rats and dogs after oral administration, and the changes observed in these studies with the combination were mainly produced by the losartan component. The administration of the losartan/hydrochlorothiazide combination induced a decrease in the red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in urea-N in the serum, a decrease in heart weight (without a histological correlate) and gastrointestinal changes (mucous membrane lesions, ulcers, erosions, haemorrhages). There was no evidence of teratogenicity in rats or rabbits treated with the losartan/hydrochlorothiazide combination. Foetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs in the F1 generation, was observed when females were treated prior to and throughout gestation. As observed in studies with losartan alone, adverse foetal and neonatal effects, including renal toxicity and foetal death, occurred when pregnant rate were treated with the losartan/hydrochlorothiazide combination during late gestation and/or lactation.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Cellulose, microcrystalline

Lactose monohydrate

Maize starch, pregelatinized

Silica, colloidal anhydrous

Magnesium stearate

Film-coating:

Hypromellose

Hydroxypropylcellulose

Iron oxide yellow (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Blister: Store below 30°C.

Bottle: Store below 30°C. Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

Aluminium//Aluminium blisters.

ACLAR//Aluminium blisters.

HDPE bottle with PP screw cap.

Blister: 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98 and 100 film-coated tablets

Blister (unit dose): 50 film-coated tablets

Bottle: 100, 250 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Mark

Methadose 10mg / 1ml Oral Concentrate

1. Name Of The Medicinal Product

Methadose 10mg/1ml Oral Concentrate

2. Qualitative And Quantitative Composition

Active Ingredient	Per 5ml
Methadone Hydrochloride BP	50mg

3. Pharmaceutical Form

Blue solution for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

For use in the treatment of opioid drug addiction (as a narcotic abstinence syndrome suppressant)

4.2 Posology And Method Of Administration

For oral administration only. This product may be used with a diluent.

Dosage Recommendations:

Adults: Initially 10-20mg per day, increasing by 10-20mg per day until there are no signs of withdrawal or intoxication. The usual dose is 40-60mg per day. The dose is adjusted according to the degree of dependence with the aim of gradual reduction.

Elderly: In the case of elderly or ill patients repeated doses should only be given with extreme caution.

Children: Not recommended for children.

This product is intended to be used with a diluent.

4.3 Contraindications

Respiratory depression, obstructive airway disease, concurrent administration with MAO inhibitors or within two weeks of discontinuation of treatment with them.

Patients dependent on non opioid drugs.

Use during an acute asthma attack is not recommended.

Known hypersensitivity to hydroxybenzoates or methadone.

Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression.

Methadone is not suitable for children.

4.4 Special Warnings And Precautions For Use

Caution should be exercised in patients with hepatic dysfunction or renal dysfunction.

In the case of elderly or ill patients, repeated doses should only be given with extreme caution.

Addiction/tolerance/dependence

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). It has a long half-life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.

Tolerance and dependence may occur as with morphine.

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.

Withdrawal

Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Respiratory depression

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release.

Hepatic disorders

Caution as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage.

As with other opioids, methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.

Neonates/children

As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on the use in children, methadone is not recommended in those under 16 (See sections 4.2, 5.2).

Further warnings

Babies born to mothers receiving methadone may suffer withdrawal symptoms.

Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.

Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.

Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.

Cases of QT interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (>100 mg/d). Methadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of:

- history of cardiac conduction abnormalities,

- advanced heart disease or ischaemic heart disease,

- Liver disease,

- family history of sudden death,

- Electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia

- concomitant treatment with drugs that have a potential for QT-prolongation,

- concomitant treatment with drugs which may cause electrolyte abnormalities,

- concomitant treatment with cytochrome P450 CYP3A4 inhibitors (see section 4.5).

In patients with recognised risk factors for QT-prolongation, or in case of concomitant treatment with drugs that have a potential for QT-prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation.

ECG monitoring is recommended, in patients without recognised risk factors for QT-prolongation, before dose titration above 100mg/d and at seven days after titration.

Caution should be exercised in patients who are concurrently taking CNS depressants

This product contains parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

MAOI's:

The concurrent use of MAOI's is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.

CNS depressants:

Alcohol, anaesthetics, hypnotics and sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly (See 4.4 Special warnings and precautions for use)

There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.

Histamine H_2- Antagonists:

Histamine H₂ antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action.

Rifampicin:

Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary.

Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone):

Induces methadone metabolism with the risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.

pH of urine:

Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.

Opioid agonist analgesics:

Additive CNS depression, respiratory depression and hypotension.

Opioid antagonists:

Naloxone and naltrexone antagonises the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (See Section 4.9 Overdose). Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms.

Antiretroviral Agents such as Nevirapine, Efavirenz, Nelfinavir, Ritonavir:

Based on the known metabolism of methadone, these agents may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Methadone may increase the plasma concentration of zidovudine. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral agents and methadone concomitantly. Methadone maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.

Ciprofloxacin:

Concomitant use may lead to sedation, confusion and respiratory depression.

Other Drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.

Pregnancy Tests:

Methadone may interfere with the urine testing for pregnancy.

Cytochrome P450 3A4 inhibitors:

Methadone clearance is decreased when co-administered with drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

St. John's Wort:

May lower plasma concentrations of methadone.

In patients taking drugs affecting cardiac conduction, or drugs which may affect electrolyte balance there is a risk of cardiac events when methadone is taken concurrently.

4.6 Pregnancy And Lactation

There is no evidence of safety in human pregnancy. A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, methadone has not been associated with congenital malformations.

It may be necessary to increase the dose of methadone if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy.

It should not be used during labour, (see 4.3 Contraindications).

Methadone is excreted in breast milk. Breast feeding is not recommended during methadone treatment.

4.7 Effects On Ability To Drive And Use Machines

This may be severely affected during and after treatment with Methadone as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient dependent and must be decided by the physician.

4.8 Undesirable Effects

CNS Effects

Respiratory depression particularly with larger doses, dependence, drowsiness, confusion, nausea and vomiting particularly at the start of treatment can occur. Changes of mood, including euphoria, and hallucinations are occasionally reported. Methadone has the potential to increase intracranial pressure, particularly in circumstances where it is already raised.

Effects on the Autonomic Nervous System

Constipation, dry mouth, eyes and nose, and less commonly micturition difficulties are observed.

Cardiovascular Effects

Bradycardia, palpitation and orthostatic hypotension can occur. Cases of QT prolongation and torsades de pointes have been rarely reported.

Other Undesirable Effects

Facial flushing, vertigo, headache, hypothermia, restlessness, exacerbation of existing asthma, decreased libido, galactorrhoea, dysmenorrhoea and amenorrhoea, rashes and miosis can also occur. Long-term administration may produce excessive sweating and raised prolactin levels.

4.9 Overdose

Symptoms: Serious overdosage is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur.

Treatment: A patent airway and assisted or controlled ventilation must be assured.

Narcotic antagonists may be required but it should be remembered that Methadone is a long acting depressant (36 to 48 hours) whereas antagonists act for 1 to 3 hours, so that treatment with the latter must be repeated as needed.

An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression.

Nalorphine (0.1mg per Kg) or Levallorphan (0.02mg per Kg) should be given intravenously as soon as possible and repeated, if necessary, every 15 minutes.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

In a person physically dependent on narcotics, administration of the usual dose of narcotic antagonist will precipitate an acute withdrawal syndrome; use of the antagonist in such a person should be avoided if possible but if it must be used to treat serious respiratory depression it should be administered with great care.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methadone is an opioid agonist with actions predominantly at the µ receptor. The analgesic activity of the racemate is almost entirely due to the l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the κ and σ opiate receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the automotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with a pA₂ value similar to its antagonism of Morphine. Like many basic drugs, Methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the Morphine type.

5.2 Pharmacokinetic Properties

Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastrointestinal tract, but undergoes fairly extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in the blood.

The pharmacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10mg, a peak plasma concentration of 75µg per litre is reached in one hour. With regular oral doses of 100-120mg daily, plasma concentrations rise from trough levels of approximately 500µg/L to a peak of about 900µg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted in sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal levels.

The half life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled, and so the half life is extended to 13 to 47 (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15 - 60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged Methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three, and thus appreciably reduce the half life time of elimination.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol

Propyl Hydroxybenzoate

Methyl Hydroxybenzoate

Patent Blue V E131

Purified Water

6.2 Incompatibilities

None Known

6.3 Shelf Life

Shelf life - 2 years

Shelf life after first opening container - 3 months

Shelf life after dilution - 3 months

6.4 Special Precautions For Storage

Store below 25°C but not in a refrigerator.

6.5 Nature And Contents Of Container

Amber (type III) glass bottle with aluminium, EPE wadded ROPP closures or HDPE, EPE wadded, child resistant tamper evident closures or HDPE, EPE wadded, tamper evident closures to contain 100ml, 150ml, 200ml or 500ml of product.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

This product is intended for use with a diluent.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

0427/0098

9. Date Of First Authorisation/Renewal Of The Authorisation

31.1.96

10. Date Of Revision Of The Text

9^th September 2008

Disipal Tablets

1. Name Of The Medicinal Product

DISIPAL TABLETS

2. Qualitative And Quantitative Composition

Orphenadrine hydrochloride BP 50 mg

3. Pharmaceutical Form

Tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Anti-cholinergic, for the treatment of all forms of Parkinsonism, including drug-induced extrapyramidal symptoms (neuroleptic syndrome).

4.2 Posology And Method Of Administration

For Adults, and the Elderly:

Initially 150 mg daily in divided doses, increasing by 50 mg every two or three days until maximum benefit is obtained. Optimal dosage is usually 250 - 300 mg daily in divided doses in idiopathic and post-encephalitic Parkinsonism, 100 - 300 mg daily in divided doses in the neuroleptic syndrome. Maximal dosage, 400 mg daily in divided doses. The elderly may be more susceptible to side-effects at doses which are clinically optimal.

For children:

A dosage for children has not been established.

4.3 Contraindications

Contraindicated in patients with tardive dyskinesia, glaucoma, or prostatic hypertrophy, untreated urinary retention, gastro-intestinal obstruction, porphyria.

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Use with caution in patients with micturition difficulties, in pregnancy and breast feeding, and in the presence of cardiovascular disease and hepatic or renal impairment. Use in caution in the elderly (see 4.2). Avoid abrupt discontinuation of treatment. For some patients, orphenadrine may be a drug of abuse.

Patients with rare hereditary problems of fructose and galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

The colours sunset yellow (E110), tartrazine (E102) and amaranth (E123) may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of other antimuscarinic drugs can lead to an increase in side effects such as dry mouth and urine retention.

4.6 Pregnancy And Lactation

No recommendations; if considered necessary, it should be used with caution, see 4.4.

4.7 Effects On Ability To Drive And Use Machines

Patients must be advised to exercise caution while driving or operating machinery or whilst carrying out other skilled tasks.

4.8 Undesirable Effects

System Organ Class	Common >1/100 <1/10	Uncommon >1/1000 <1/100	Rare >1/10,000 <1/1000
Immune system disorder		Hypersensitivity
Nervous system disorder	Dizziness	Sedation, confusion, nervousness, hallucinations, convulsions, insomnia, euphoria	Memory disturbances
Eye disorders	Accommodation disorders
Cardiac disorders		Tachycardia
Gastrointestinal disorders	Dry mouth, gastrointestinal disturbances
Renal and urinary disorders		Urinary retention

4.9 Overdose

Toxic effects are anti-cholinergic in nature and the treatment is gastric lavage, cholinergics such as carbachol, anticholinesterases such as physostigmine, and general non-specific treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Orphenadrine, which is a congener of diphenhydramine without sharing its soporific effect, is an antimuscarinic agent. It also has weak antihistaminic and local anaesthetic properties.

Orphenadrine is used as the hydrochloride in the symptomatic treatment of Parkinsonism. It is also used to alleviate the extrapyramidal syndrome induced by drugs such as the phenothiazine derivatives, but is of no value in tardive dyskinesia, which may be exacerbated.

5.2 Pharmacokinetic Properties

Orphenadrine is readily absorbed from the gastro-intestinal tract, and very readily absorbed following intramuscular injection. It is rapidly distributed in tissues and most of a dose is metabolised and excreted in the urine along with a small proportion of unchanged drug. A half life of 14 hours has been reported.

5.3 Preclinical Safety Data

No relevant pre-clinical safety data has been generated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Sucrose

Acacia

Maize starch

Tribasic calcium phosphate

Stearic acid

Magnesium stearate

Opaseal P-17-0200 (containing IMS, polyvinylacetate phthalate and stearic acid)

Calcium carbonate

Talc

Kaolin

Titanium dioxide

Gelatin

Opalux yellow AS 3026 (containing sucrose, titanium dioxide, tartrazine E102, sunset yellow E110, povidone, amaranth E123 and sodium benzoate E211)

Opaglos 6000 (containing ethanol, shellac, beeswax and yellow carnuba wax)

Black printing ink Opacode black S-1-27794 (containing shellac, IMS, black iron oxide E172, N-butyl alcohol, propylene glycol E1520, isopropyl alcohol)

6.2 Incompatibilities

None

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

Store at room temperature (15°C - 25°C)

6.5 Nature And Contents Of Container

Amber glass click-lock bottles and/or securitainers and/or plastic lid-seal containers, containing 100, 250, 1,000, or 10,000 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data

7. Marketing Authorisation Holder

Astellas Pharma Ltd

Lovett House

Lovett Road

Staines

TW18 3AZ

United Kingdom

8. Marketing Authorisation Number(S)

PL 0166/5001R

9. Date Of First Authorisation/Renewal Of The Authorisation

6 May 1987; renewed March 2003.

10. Date Of Revision Of The Text

12^th June 2009

11. Legal Category

POM

Zyprexa Powder for Solution for Injection

1. Name Of The Medicinal Product

ZYPREXA*

2. Qualitative And Quantitative Composition

Each vial contains 10 mg olanzapine. After reconstitution each ml of the solution contains 5 mg olanzapine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection.

Yellow lyophilised powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

ZYPREXA powder for solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or manic episode, when oral therapy is not appropriate. Treatment with ZYPREXA powder for solution for injection should be discontinued and the use of oral olanzapine should be initiated, as soon as clinically appropriate.

4.2 Posology And Method Of Administration

Adults

For intramuscular use. Do not administer intravenously or subcutaneously. ZYPREXA powder for solution for injection is intended for short-term use only, for up to a maximum of three consecutive days.

The maximum daily dose of olanzapine (including all formulations of olanzapine) is 20 mg.

The recommended initial dose for olanzapine injection is 10 mg, administered as a single intramuscular injection. A lower dose (5 mg or 7.5 mg) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.4). A second injection, 5-10 mg, may be administered 2 hours after the first injection, on the basis of individual clinical status.

Not more than three injections should be given in any 24-hour period and the maximum daily dose of olanzapine of 20 mg (including all formulations) should not be exceeded.

ZYPREXA powder for solution for injection should be reconstituted in accordance with the recommendation in section 6.6.

For further information on continued treatment with oral olanzapine (5 to 20 mg daily), see the Summary of Product Characteristics for ZYPREXA coated tablets or ZYPREXA VELOTAB orodispersible tablets.

Paediatric population

There is no experience in children. ZYPREXA powder for solution for injection is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Elderly

The recommended starting dose in elderly patients (>60 years) is 2.5-5 mg. Depending on the patient's clinical status (see section 4.4), a second injection, 2.5-5 mg, may be administered 2 hours after the first injection. Not more than 3 injections should be given in any 24-hour period and the maximum daily dose of 20 mg (including all formulations) of olanzapine should not be exceeded.

Renal and/or hepatic impairment

A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 5 mg and only increased with caution.

Gender

The dose and dose range need not be routinely altered for female patients relative to male patients.

Smokers

The 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. Additional injections, when indicated, should be conservative in such patients.

(See sections 4.5 and 5.2.)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of narrow-angle glaucoma.

4.4 Special Warnings And Precautions For Use

The efficacy of IM olanzapine has not been established in patients with agitation and disturbed behaviours related to conditions other than schizophrenia or manic episode.

Unstable medical conditions

IM olanzapine should not be administered to patients with unstable medical conditions, such as acute myocardial infarction, unstable angina pectoris, severe hypotension and/or bradycardia, sick sinus syndrome, or following heart surgery. If the patient's medical history with regard to these unstable medical conditions cannot be determined, the risks and benefits of IM olanzapine should be considered in relation to other alternative treatments.

Concomitant use of benzodiazepines and other medicinal products

Special caution is necessary in patients who have received treatment with other medicinal products having haemodynamic properties similar to those of intramuscular olanzapine including other antipsychotics (oral and/or intramuscular) and benzodiazepines (see section 4.5). Temporal association of treatment with IM olanzapine with hypotension, bradycardia, respiratory depression and death has been very rarely (< 0.01%) reported, particularly in patients who have received benzodiazepines and/or other antipsychotics (see section 4.8).

Simultaneous injection of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation, cardiorespiratory depression and in very rare cases, death (see sections 4.5 and 6.2). If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least one hour after IM olanzapine administration. If the patient has received parenteral benzodiazepine, IM olanzapine administration should only be considered after careful evaluation of clinical status, and the patient should be closely monitored for excessive sedation and cardiorespiratory depression.

Hypotension

It is extremely important that patients receiving intramuscular olanzapine should be closely observed for hypotension, including postural hypotension, bradyarrhythmia, and/or hypoventilation, particularly for the first 4 hours following injection and close observation should be continued after this period if clinically indicated. Blood pressure, pulse, respiratory rate and level of consciousness should be observed regularly and remedial treatment provided if required. Patients should remain recumbent if dizzy or drowsy after injection until examination indicates that they are not experiencing hypotension, including postural hypotension, bradyarrhythmia, and/or hypoventilation.

The safety and efficacy of IM olanzapine has not been evaluated in patients with alcohol or drug intoxication (either with prescribed or illicit drugs) (see section 4.5).

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 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 olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All 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 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. 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 product. Rare cases reported as NMS have also been received in association with 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 ZYPREXA, 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 ZYPREXA, 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 oral 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 olanzapine is stopped abruptly.

QT interval

In clinical trials with oral administration, 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 oral 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 oral 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paediatric Population

Interaction studies have only been performed in adults.

IM olanzapine has not been studied in patients with alcohol or drug intoxication (see section 4.4).

Caution should be exercised in patients who consume alcohol or receive medicinal products that can induce hypotension, bradycardia, respiratory or central nervous system depression (see section 4.4).

Potential for Interaction, Following Intramuscular Injection

In a single dose intramuscular study of olanzapine 5 mg, administered 1 hour before intramuscular lorazepam 2 mg (metabolised by glucuronidation), the pharmacokinetics of both medicines were unchanged. However, the combination added to the somnolence observed with either medicine alone. Concomitant injection of olanzapine and parenteral benzodiazepine is not recommended (see sections 4.4 and 6.2).

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 C_max 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.

Decreased Bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

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 (see section 6.2).

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.

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).

4.6 Pregnancy And Lactation

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 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.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

4.8 Undesirable Effects

A common (1-10%) undesirable effect associated with the use of intramuscular olanzapine in clinical trials was somnolence.

In post-marketing reports, temporal association of treatment with IM olanzapine with cases of respiratory depression, hypotension or bradycardia, and death have been very rarely reported, mostly in patients who concomitantly received benzodiazepines and/or other antipsychotic medicinal products, or who were treated in excess of olanzapine recommended daily doses (see sections 4.4 and 4.5).

The following table is based on the undesirable effects and laboratory investigations from clinical trials with ZYPREXA powder for solution for injection rather than oral olanzapine.

Cardiac disorders Common (1-10%): Bradycardia, with or without hypotension or syncope, tachycardia. Uncommon (0.1-1%): Sinus pause.

Vascular disorders Common (1-10%): Postural hypotension, hypotension.

Respiratory disorders Uncommon (0.1-1%): Hypoventilation.

General disorders and administration site conditions Common (1-10%): Injection site discomfort.

The undesirable effects listed below have been observed following administration of oral olanzapine, but may also occur following administration of ZYPREXA powder for solution for injection.

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 (

Very common	Common	Uncommon	Not known
Blood and the lymphatic system disorders
	Eosinophilia	Leucopenia Neutropenia	Thrombocytopenia
Immune system disorders
			Allergic reaction
Metabolism and nutrition disorders
Weight gain1	Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite		Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) Hypothermia
Nervous system disorders
Somnolence	Dizziness Akathisia6 Parkinsonism6 Dyskinesia6		Seizures where in most cases a history of seizures or risk factors for seizures were reported Neuroleptic malignant syndrome (see section 4.4) Dystonia (including oculogyration) Tardive dyskinesia Discontinuation symptoms7
Cardiac disorders
		Bradycardia QTc prolongation (see section 4.4)	Ventricular tachycardia/fibrillation, sudden death (see section 4.4)
Vascular disorders
	Orthostatic hypotension	Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4)
Gastrointestinal disorders
	Mild, transient anticholinergic effects including constipation and dry mouth		Pancreatitis
Hepato-biliary disorders
	Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)		Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
Skin and subcutaneous tissue disorders
	Rash	Photosensitivity reaction Alopecia
Musculoskeletal and connective tissue disorders
			Rhabdomyolysis
Renal and urinary disorders
		Urinary incontinence	Urinary hesitation
Pregnancy, puerperium and perinatal conditions
			Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
			Priapism
General disorders and administration site conditions
	Asthenia Fatigue Oedema
Investigations
Elevated plasma prolactin levels8		High creatine phosphokinase Increased total bilirubin	Increased alkaline phosphatase

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 (

⁶In 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.

⁷Acute 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 (

4.9 Overdose

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 overdoses as low as 450mg, 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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Diazepines, oxazepines and thiazepines. ATC code: N05A H03.

Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (K_i <100nM) for serotonin 5-HT_2A/2C, 5-HT₃, 5-HT₆; dopamine D₁, D₂, D₃, D₄, D₅; cholinergic muscarinic receptors M₁-M₅; α₁-adrenergic; and histamine H₁ receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5-HT₂ than dopamine D₂ receptors and greater 5-HT₂ than D₂ activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an 'anxiolytic' test.

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5-HT_2A than dopamine D₂ receptor occupancy. In addition, a SPECT imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D₂ occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

In two of two placebo- and two of three comparator-controlled trials with oral olanzapine, in over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective and related disorders, which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (P = 0.001) favouring oral olanzapine (-6.0) versus haloperidol (-3.1).

In patients with manic or mixed episode of bipolar disorder, oral olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Oral olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of oral olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; P = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

5.2 Pharmacokinetic Properties

In a pharmacokinetic study in healthy volunteers, a dose of 5 mg of ZYPREXA powder for solution for injection produced a maximum plasma concentration (C_max) approximately 5-times higher than that seen with the same dose of olanzapine administered orally. The C_max occurs earlier after intramuscular compared to oral use (15 to 45 minutes versus 5 to 8 hours). As with oral use, C_max and area under the curve after intramuscular use are directly proportional to the dose administered. For the same dose of olanzapine administered intramuscularly and orally, the associated area under the curve, half-life, clearance, and volume of distribution are similar. The metabolic profiles following intramuscular and oral use are similar.

In non-smoking versus smoking subjects (males and females) administered olanzapine intramuscularly, the mean elimination half-life was prolonged (38.6 versus 30.4 hours) and the clearance was reduced (18.6 versus 27.7 l/hr).

Additional pharmacokinetic data following administration of oral olanzapine are described below.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine. After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.