Octreotide200 micrograms / ml Solution for injection

1. Name Of The Medicinal Product

Octreotide 200 micrograms/ml Solution for Injection

2. Qualitative And Quantitative Composition

Each 1 ml of Octreotide solution for injection contains 200 micrograms of Octreotide as Octreotide acetate.

Octreotide solutions for injection contain less than 1 mmol (23 mg) of sodium per 1 ml of solution (i.e. essentially "sodium-free").

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear, colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of symptoms associated with gastroenteropancreatic tumours (GEP tumours) including:

• Carcinoid tumours with features of carcinoid syndrome

• VIPomas

• Glucagonomas

Octreotide is not an antitumour therapy and is therefore not curative in these patients.

Acromegaly:

For symptomatic control and reduction of growth hormone (GH) and Insulin-like growth factor number-1 (IGF-1) plasma levels in patients with acromegaly who are not adequately controlled by surgery or radiotherapy:

- In short term treatment, prior to pituitary surgery, or

- In long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, dopamine agonist treatment, or in the interim period until surgery becomes effective.

- Octreotide is indicated for acromegalic patients for whom surgery is inappropriate.

Evidence from short term studies demonstrates that tumour size is reduced in some patients (prior to surgery); further tumour shrinkage, however, cannot be expected as a feature of continued long term treatment.

Prevention of complications following pancreatic surgery.

4.2 Posology And Method Of Administration

Administration by the subcutaneous route:

Octreotide should be administered by the subcutaneous route without reconstitution or dilution.

Administration by the intravenous route:

GEP tumours where a rapid response is needed (i.v. administration as a bolus): Octreotide should be diluted with 0.9% (w/v) Sodium Chloride solution for injection at a ratio not exceeding 1:100. Dilution with Glucose solution is not recommended.

To reduce discomfort, let Octreotide injection reach room temperature before administration. Avoid multiple injections at short intervals at the same administration site.

Octreotide injection should be inspected prior to administration and only clear solutions without particles should be used.

GEP tumours:

Initially a dose of 50 micrograms once or twice daily by subcutaneous injection is recommended. Depending on clinical response the dosage can be gradually increased to 100-200 micrograms three times daily. Under exceptional circumstances, higher doses may be necessary. Maintenance doses are variable. The recommended maximum daily dosage is 600 micrograms.

The recommended route of administration is subcutaneous, however, in instances where a rapid response is required, e.g. carcinoid crises, the initial recommended dose of Octreotide may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring the cardiac rhythm through ECG.

In carcinoid tumours, if there is no beneficial response with the maximum tolerated dose of Octreotide within a week, the therapy should be discontinued.

Acromegaly:

Initially doses of 50 – 100 micrograms three times daily by subcutaneous. injection. For most patients the optimal daily dose is normally 200 – 300 micrograms daily. More than 1500 microgram per day should not be given. Dose adjustment should be made based on monthly measurements of the amount of circulating growth hormones (GH or IGF-1), changes to the clinical picture and possible adverse events.

If no significant reduction of growth hormone (GH) levels and no improvement of clinical symptoms have been achieved within three months of starting treatment with Octreotide, therapy should be discontinued.

Prevention of complications following pancreatic surgery:

A dose of 100 micrograms three times daily by subcutaneous injection for seven consecutive days is recommended, starting on the day of the operation at least one hour before laparotomy.

Use in patients with renal insufficiency:

Renal insufficiency did not affect the total exposure (AUC: area under the curve) to Octreotide when administered subcutaneously, and therefore no dose adjustment of Octreotide is necessary.

Use in patients with hepatic insufficiency:

In patients with liver cirrhosis the half-life of Octreotide may be increased, requiring an adjustment of the maintenance dose.

Use in the elderly:

In elderly patients treated with Octreotide, there was no evidence for reduced tolerability or altered dosage requirements.

Use in children:

Experience with the use of Octreotide in children is limited.

4.3 Contraindications

Hypersensitivity to Octreotide or to any of the excipients of Octreotide (see section 6.1 Full list of excipients).

4.4 Special Warnings And Precautions For Use

Octreotide should only be used under specialist hospital supervision with appropriate facilities available for diagnosis and evaluation of response.

As growth hormone secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defect), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures should be considered.

Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by Octreotide may occur rarely, with rapid recurrence of severe symptoms.

Octreotide may reduce insulin requirements in patients receiving treatment for type I diabetes mellitus. In non-diabetics and type II diabetics with partially intact insulin reserves, Octreotide administration can result in prandial increases in glycaemia.

Blood glucose levels should therefore be carefully monitored particularly at the initiation of treatment with Octreotide or when the dose is changed. Unstable blood sugar concentrations may be avoided by dividing the daily dose into several injections

Thyroid function should be monitored in patients receiving long-term Octreotide therapy.

In patients with cirrhosis, dosage adjustment may be necessary (see section 4.2. Posology and Method of Administration).

The development of gallstones has been reported (estimated at between 15% and 30%) in association with Octreotide treatment. Ultrasonic examination for gallstones before, and at 6 to 12 month intervals during prolonged Octreotide treatment is recommended. The presence of gallstones in patients treated with Octreotide is usually asymptomatic; symptomatic stones should be treated in normal manner.

Liver function should be monitored during treatment with Octreotide.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine. Combined treatment with Octreotide and cimetidine requires adjustment of doses.

Concomitant administration of Octreotide and bromocriptine increases the bioavailability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that Octreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinine, terfenadine, carbamazepine, digoxin, warfarin) should therefore be used with caution.

4.6 Pregnancy And Lactation

Pregnancy

Pregnant women should be given the drug only in compelling circumstances.

Insufficient data exist on the use of Octreotide in pregnant women. Due to its growth hormone inhibiting effect, it may be assumed that Octreotide poses a risk to the foetus.

Studies in animals showed transient growth retardation of offspring before weaning (see section 5.3.), possibly consequent upon the specific endocrine profiles of species tested, but there was no evidence of foetotoxic, teratogenic or other reproductive effects.

The potential risk for humans is unknown.

Lactation

It is not known whether Octreotide passes into breast milk. Women receiving treatment with Octreotide should only breastfeed their infants if it is absolutely essential.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The frequency of the undesirable effects listed below is defined using the following convention: very common (.

Further details are given after the table

MedDRA Organ System Class	Very common	Common	Uncommon	Rare	Very rare
Cardiac disorders					bradycardia.
Gastrointestinal disorders (1)		diarrhoea, steatorrhoea, flatulence, loose stools, nausea, abdominal pain and abdominal bloating	anorexia, vomiting, epigastric pain	acute intestinal obstruction, severe epigastric pain, abdominal tenderness and guarding.
Cutaneous and subcutaneous tissue conditions				hypersensitivity skin reactions, exanthema and transient alopecia
Endocrine disorders		hyperglycaemia, impaired post-prandial glucose tolerance, and in some cases a state of persistent hyperglycaemia. Hypoglycaemia		acute pancreatitis. Cases of cholelithiasis-induced pancreatitis (2)
General disorders and administration site conditions (3)		pain at the administration site, sensation of stinging, throbbing or burning with redness, swelling and rash			anaphylactic reactions
Hepatobiliary conditions (4)		gallstone	hepatic dysfunctions		reversible acute hepatitis, slow development of hyperbilirubinaemia in association with elevation of alkaline phosphatase, gamma-glutamyl transferase and, to a lesser extent, transaminases. biliary colic.

(1) To reduce gastrointestinal adverse reactions, Octreotide should be administered between meals or before bed.

(2) This effect is generally observed within the first hours or days of treatment with Octreotide and is reversible on discontinuation of the treatment.

(3) Administration site effects are generally mild and of short duration. Local discomfort may be reduced by allowing the solution to reach room temperature before administration or by injecting a lower volume of a more concentrated solution.

(4) Gallstone formation with prolonged use (see 4.4. Special Warning and Precautions for Use).

There have been isolated reports of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

4.9 Overdose

Doses of up to 2.0 mg Octreotide given three times a day via the subcutaneous route for several months have been well tolerated.

The maximum single dose so far given to an adult has been 1.0 mg as an intravenous bolus. The reversible symptoms of overdose observed were mild bradycardia, facial flushing, abdominal pains, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours after administration of the drug.

No potentially fatal reactions have been reported following acute overdose.

The management of overdosage should be symptomatic.

One patient has been reported to have received an accidental overdosage of Octreotide by continuous infusion (250 micrograms per hour for forty eight hours instead of 25 micrograms per hour). He experienced no side-effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: 8.1.3. Antigrowth Hormones.

ATC code: H01CB02

Octreotide is a synthetic octapeptide analog of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the gastroenteropancreatic (GEP) endocrine system, stomach, intestine and pancreas (for example, gastrin, insulin and glucagon).

Octreotide gives symptomatic relief of the symptoms caused by functional tumours of the gastroenteropancreatic (GEP) endocrine system (stomach, intestine and pancreas) in patients whose symptoms have not been relieved by other forms of treatment such as surgery, hepatic artery embolisation or chemotherapy.

The effect of Octreotide on tumour size, rate of growth or on the formation of metastases has not yet been clearly documented.

In healthy volunteers Octreotide has been shown to inhibit the release of GH stimulated by arginine, exercise and insulin-induced hypoglycaemia, and thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).

Unlike somatostatin, Octreotide inhibits growth hormone (GH) and glucagon preferentially over insulin.

Discontinuation of treatment is not followed by a rebound effect with hypersecretion of hormones.

In patients with carcinoid tumours, Octreotide may result in relief of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid (5-HIAA).

In patients with VIPomas, the biochemical characteristic is overproduction of vasoactive intestinal peptide (VIP). In most cases, Octreotide alleviates the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, such as hypokalaemia. The need for administration of fluids and electrolytes is reduced. In some patients, computer tomography scanning reveals a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

In glucagonomas, administration of Octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of this condition. The effect of Octreotide on the moderate diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in affected patients. Although administration of Octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

In patients with acromegaly, Octreotide reduces GH and IGF-1 plasma levels. A GH reduction by around 50% or more occurs in over 90% of patients, and a reduction of plasma GH to < 5 ng/ml can be achieved in about half of the cases. In most patients, Octreotide significantly reduces clinical symptoms such as headache, swelling of skin and soft tissues, hyperhidrosis, arthralgia and paraesthesia. In patients with large volume pituitary adenomas, Octreotide may lead to shrinkage of the tumour mass.

For patients undergoing pancreatic surgery, the peri- and post-operative administration of Octreotide generally reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).

5.2 Pharmacokinetic Properties

Absorption

After subcutaneous administration, Octreotide is rapidly and completely absorbed. The peak plasma concentration is reached after 30 minutes.

Distribution

The volume of distribution is around 0.27 l/kg and the total body clearance is 160 ml/min. Plasma protein binding is approximately 65%. The amount of Octreotide bound to blood cells is negligible.

Elimination

The elimination half-life after subcutaneous administration is 100 minutes.

After intravenous administration, the elimination is biphasic with half-lives of 10 and 90 minutes. Most of the administered dose is eliminated in the faeces and approximately 32% is excreted in unchanged form in the urine.

Renal insufficiency did not affect the total exposure (AUC) to Octreotide when administered in the form of a subcutaneous injection. The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver.

5.3 Preclinical Safety Data

Acute toxicity

Acute toxicity studies performed with Octreotide in the guinea-pig showed that LD50 is 72 mg/kg by IV and 470 mg/kg subcutaneously . In the mouse, LD50 was 18 mg/kg ( IV). Octreotide acetate was well tolerated by dogs that received up to 1 mg/kg by IV bolus.

Toxicity after repeated administration

A 26 weeks toxicity study in dogs, with IV doses up to 0.5 mg/kg, bid, showed progressive changes in acidophilic pituitary cells that contain prolactin. Further investigations showed that this variation was within the physiologic range and apparently not related to Octreotide administration. No significant changes were seen in plasma level of hormones. Rhesus monkey females receiving 0.5mg/kg bid for 3 weeks did not show pituitary changes nor changes in plasma levels of GH, prolactin or glucose.

Local tolerance

While acidic vehicle produced inflammation and fibroplasias in mouse after repeated injections, no evidence of Octreotide acetate causing hypersensitivity reactions was found in the guinea-pig model after intradermal administration.

In a toxicology study on predominantly male rats, sarcomas were observed at the subcutaneous injection site after 52 weeks, but only with the highest dose (around forty times the maximum dose used in humans). In a 52-week toxicology study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. No cases of tumour formation at the injection site have been reported in patients treated with Octreotide for periods of up to 15 years. All of the available information to date indicates that the results obtained in rats are species-specific and are not relevant for the use of the drug in humans.

Mutagenicity

Octreotide and/or its metabolites were without mutagenic potential in standard in vitro tests. An increase of chromosomic changes in V79 Chinese hamster cells was seen, in vitro, although only with high and cytotoxic concentrations. In human lymphocytes incubated with Octreotide acetate in vitro the chromosomal changes were not increased. Blastogenic activity in vivo (micronuclei test in guinea pigs) was not observed

Carcinogenicity

Studies with mice treated with SC Octreotide in daily doses up to 1.25 mg/kg of body weight, the presence of fibrosarcomas, after 52, 104 and 113/116 weeks was observed in some animals, mainly males. Local tumours in control group of mice also appeared, however the tumours were related to disorganized fibroplasias produced by irritant effects of the acid vehicle. In guinea-pigs that received daily SC injections of Octreotide in doses up to 2 mg/kg for 98 weeks, neoplastic lesions were not observed.

The mouse carcinogenicity study also revealed endometrial carcinomas, statistically significant for the highest SC dose of 1.25 mg/kg/day. This observation was associated with an increase in endometritis, a reduced number of luteal bodies, a reduction of breast adenomas and the presence of luminal dilation and glandular uterus, suggesting a hormonal imbalance. The available data indicates that the observed hormone-dependent tumours in mice are species specific and therefore not relevant for humans.

Reproduction toxicity

The fertility study as well as the studies of pre-, peri- and post-natal effects in rats did not reveal adverse events on the reproductive ability or on foetal development with doses up to 1 mg/kg/day SC. Some delay of offspring growth, which was transient and may be due the GH inhibition due to the excessive pharmacodynamic activity, was observed

Preclinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in animals showed transient growth retardation of offspring, possibly due to the pharmacodynamic action of Octreotide, but there was no evidence of foetotoxic, teratogenic, or other reproductive effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glacial acetic acid (pH adjustment),

Sodium acetate trihydrate (pH adjustment),

Sodium chloride,

Phenol (preservative),

Water for injections.

This medicinal product contains less than 1 mmol (23 mg) of sodium per 1 ml of solution, i.e. is essentially "sodium-free".

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

6.3 Shelf Life

Medicinal product as packaged for sale: 2 years

For daily use: the product after first opening may be stored for two weeks at ambient temperature of 25ºC. To prevent contamination, it is recommended that the cap of the vial for injection should be punctured no more than 10 times

Storage conditions after dilution:

The chemical and physical stability of Octreotide solution diluted in 0.9% sodium chloride solution for injection and stored in PVC bags or in polypropylene syringes has been demonstrated for seven days when stored at below 25ºC. From a microbiological point of view, the product should be used immediately. If not used immediately, storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2ºC to 8ºC, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Medicinal product as packaged for sale: store in a refrigerator (2°C - 8°C).

Do not freeze. Keep the vial in the outer carton in order to protect from light.

Storage conditions after dilution: please see section 6.3.

.

6.5 Nature And Contents Of Container

5 ml Type I amber glass vials for injection, with a teflon-faced rubber stopper, aluminium seal and flip-off plastic cap, containing 5 ml of Octreotide solution for injection.

Packs of 1 and 10 vials containing 5 ml of solution for injection.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The vials for injection should be opened only immediately prior to use and any unused solution should be discarded.

Prior to administration the solution should be inspected visually for changes of colour or solid particles.

It is not recommended to mix or dilute the Octreotide solutions for injection except with 0.9% Sodium Chloride solution.

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

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

8. Marketing Authorisation Number(S)

PL 04515/0219

9. Date Of First Authorisation/Renewal Of The Authorisation

21^st May 2007

10. Date Of Revision Of The Text

26th June 2009

Opticrom Allergy Eye Drops

Opticrom Allergy 2% w/v Eye Drops

sodium cromoglicate

Is this leaflet hard to see or read?

Phone 01483 505515 for help

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription. However, you still need to use Opticrom Allergy carefully to get the best results from it.

• Keep this leaflet. You may need to read it again


• Ask your pharmacist if you need more information or advice


• You must contact a doctor if your symptoms worsen or do not improve


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist

In this leaflet:

• 1. What Opticrom Allergy is and what it is used for


• 2. Before you use Opticrom Allergy


• 3. How to use Opticrom Allergy


• 4. Possible side effects


• 5. How to store Opticrom Allergy


• 6. Further information

What Opticrom Allergy is and what it is used for

Opticrom Allergy 2% w/v Eye Drops (called Opticrom Allergy in this leaflet) contain a medicine called sodium cromoglicate. This belongs to a group of medicines called anti-allergics.

It works by stopping the release of the natural substances in your eyes that can lead to an allergic reaction. Signs of an allergic reaction include itchy, watery, red or inflamed eyes and puffy eyelids.

Opticrom Allergy is used for the relief and treatment of eye allergies. These allergies can happen:

• At any time of the year and is called ‘perennial allergic conjunctivitis’


• In different seasons of the year caused by different pollens. This is called ‘seasonal allergic conjunctivitis’ or hay fever

Before you use Opticrom Allergy

Do not use this medicine and tell your doctor or pharmacist if:

• You are allergic (hypersensitive) to sodium cromoglicate, or any of the other ingredients of Opticrom Allergy (listed in Section 6: Further information)
  Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat, tongue and worsening of redness, itching or swelling of the eye or eyelid

Do not use this medicine if the above applies to you. If you are not sure, talk to your doctor or pharmacist before using Opticrom Allergy.

Take special care with Opticrom Allergy if:

• You wear soft contact lenses. You should not wear contact lenses while using these drops

If you are not sure if the above applies to you, talk to your doctor or pharmacist before using Opticrom Allergy.

Pregnancy and breast-feeding

Talk to your doctor before using this medicine if you are pregnant, might become pregnant or think you may be pregnant.

If you are breast-feeding or planning to breast-feed, talk to your doctor or pharmacist before taking or using any medicine.

Driving and using machines

You may have blurred eyesight straight after using this medicine. If this happens, do not drive or use any tools or machines until you can see clearly.

Important information about some of the ingredients of Opticrom Allergy

Opticrom Allergy contains benzalkonium chloride. This may cause your eyes to become irritated. It may also change the colour of your contact lenses.

How to use Opticrom Allergy

Always use Opticrom Allergy exactly as your doctor or pharmacist has told you. You should check with your doctor or pharmacist if you are not sure

How to use this medicine

• Wash your hands


• Remove the cap from the bottle


• Tilt your head back


• Squeeze one or two drops inside the lower lid without touching your eye


• Close your eye


• Wipe away any excess liquid from the eyes with a clean tissue


• Always put the cap back on the bottle as soon as you have used it


• Repeat in the other eye if needed

How much to use

• One or two drops in each eye four times a day, or as directed by your doctor


• If your symptoms worsen or do not improve, talk to your doctor or pharmacist

If you forget to use Opticrom Allergy

If you forget a dose, use your drops as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose. Do not use a double dose to make up for a forgotten dose.

If you stop using Opticrom Allergy

You should keep using these drops if you are still around the things that you are allergic to. If you stop using Opticrom Allergy, your allergy symptoms may come back.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible side effects

Like all medicines, Opticrom Allergy can cause side effects, although not everybody gets them.

Stop using Opticrom Allergy and see a doctor as soon as possible if:

• The itching, redness or swelling gets worse. You may be allergic to these drops.

Talk to your doctor or pharmacist if any of the side effects gets serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet:

• Stinging or burning in your eyes or blurring of eyesight. This should only last for a short time and occurs immediately after using the eye drops


• Mild eye irritation

How to store Opticrom Allergy

Keep this medicine in a safe place where children cannot see or reach it.

Do not use Opticrom Allergy after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Store below 30°C. Keep the bottle in the outer carton in order to protect from light.

Opticrom Allergy is sterile when you buy it, so you must not keep it for more than four weeks after opening the bottle.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Opticrom Allergy contains

• The solution contains 2.0% w/v of the active substance, sodium cromoglicate


• The other ingredients are disodium edetate, benzalkonium chloride and purified water

What Opticrom Allergy looks like and contents of the pack

Opticrom Allergy is a clear colourless to pale yellow solution supplied in a 5ml or 10 ml plastic dropper bottle with a tamper-proof cap

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Tel:01483 505515

Fax:01483 535432

email:uk-medicalinformation@sanofi-aventis.com

Manufacturer

Sanofi Winthrop Industrie

Boulevard Industriel

76580 Le Trait

France

This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.

This leaflet was last revised in July 2008

© Sanofi-aventis, 2001 – 2008

Olanzapine Sandoz 10 mg Orodispersible Tablets

1. Name Of The Medicinal Product

Olanzapine Sandoz 10 mg Orodispersible Tablets

2. Qualitative And Quantitative Composition

Each orodispersible tablet contains 10 mg olanzapine.

Excipients:

121.20 mg lactose monohydrate as 115.14 lactose as anhydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Yellow, round, flat, tablet with diameter 8.2mm±0.1mm and thickness 2.4mm±0.2mm.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology And Method Of Administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (See section 5.1).

Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.

During treatment for schizophrenia, manic episode and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours. Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.

Olanzapine Orodispersible Tablet should be placed in the mouth, where it will rapidly disperse in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before administration.

Olanzapine Orodispersible Tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. It has the same dosage and frequency of administration as olanzapine coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets.

Paediatric population

Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2).

Elderly

A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see also section 4.4).

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

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine coated tablets should be used.

(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

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

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 ischemic 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 products. 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 dysrythmia). Additional signs may include elevated creatinine 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. Patients treated with any antipsychotic agents, including olanzapine, 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 regulary.

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 olanzapine, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate transferase (AST) have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organized 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 leukocyte 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 withmyeloproliferative 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, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has very rarely (<0.01%) been reported. A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism, all possible risk factors of VTE, e.g., immobilisation of patients, should be identified and preventive measures undertaken.

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 antagonize the effects of direct and indirect dopamine agonists.

Seizures

Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

This medicine contains lactose monohydrate. 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

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female nonsmokers 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.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

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.

Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in infants born to mothers who had used olanzapine during the 3rd trimester.

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

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 (

System Organ Class	Very common	Common	Uncommon	Not known
Blood and the lymphatic system disorders		Eosinophilia	Leukopenia 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)
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
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 (

⁶ In clinical trials, the incidence of parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

⁷ Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.

⁸ In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. Generally in olanzapine-treated patients potentially associated breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement, galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased libido in both genders) were commonly observed.

Long-term exposure (at least 48 weeks)

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.

In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (

Paediatric populations

Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (

Metabolism and nutrition disorders Very common: Weight gain9, elevated triglyceride levels10, increased appetite. Common: Elevated cholesterol levels11

Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastrointestinal disorders Common: Dry mouth

Hepato-biliary disorders Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels12.

⁹ Following short term treatment (median duration 22 days), weight gain

¹⁰ Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (

¹¹ Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (

¹² Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.

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 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management of overdose

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60%.

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: antipsychotics; 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 (Ki; < 100 nM) for serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1-m5; α1 adrenergic; and histamine H1 receptors. Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in-vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity 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 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (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 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 olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. 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 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.

Paediatric population

The experience in adolescents (ages 13 to 17 years) is limited to short term efficacy data in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no data on maintenance of effect and limited data on long term safety (see sections 4.4 and 4.8).

5.2 Pharmacokinetic Properties

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets.

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined

Olanzapine is metabolized 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.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.

In female versus male subjects the mean elimination half life was somewhat prolonged (36.7 versus 32.3 hrs) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites.

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hr) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hr and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/mL. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3 Preclinical Safety Data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at

Olmetec Plus 40 mg / 12.5 mg Film-Coated Tablets

1. Name Of The Medicinal Product

Olmetec Plus 40 mg/12.5 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 40 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide.

Excipients:

Each film-coated tablet contains 233.9 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Reddish-yellow, oval, film-coated tablet with C23 debossed on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of essential hypertension.

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg fixed dose combinations are indicated in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg alone.

4.2 Posology And Method Of Administration

Adults

The recommended dose of Olmetec Plus 40 mg/12.5 mg or 40 mg/25 mg is 1 tablet per day.

Olmetec Plus 40 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.

Olmetec Plus 40 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Olmetec Plus 40 mg/12.5 mg fixed dose combination.

For convenience, patients receiving olmesartan medoxomil and hydrochlorothiazide from separate tablets may be switched to Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg tablets containing the same component doses.

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg can be taken with or without food.

Elderly (age 65 years or over)

In elderly patients the same dosage of the combination is recommended as for adults.

Blood pressure should be closely monitored.

Renal impairment

Olmetec Plus is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30–60 mL/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group, and periodic monitoring is advised.

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see sections 4.3, 4.4, 5.2).

Hepatic impairment

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg should be used with caution in patients with mild hepatic impairment (see sections 4.4, 5.2). Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment. Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg therefore should not be used in patients with moderate and severe hepatic impairment (see sections 4.3, 5.2), as well as in cholestasis and biliary obstruction (see section 4.3).

Children and adolescents

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients (see section 6.1) or to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).

Renal impairment (see sections 4.4 and 5.2).

Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

Moderate and severe hepatic impairment, cholestasis and biliary obstructive disorders (see section 5.2).

Second and third trimester of pregnancy (see sections 4.4 and 4.6).

4.4 Special Warnings And Precautions For Use

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 Olmetec Plus.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

Olmetec Plus should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30–60 mL/min) is 20 mg olmesartan medoxomil once daily. However, in such patients Olmetec Plus 20 mg/12.5 mg and 20 mg/25 mg should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see section 4.3).

There is no experience of the administration of Olmetec Plus in patients with a recent kidney transplantation.

Hepatic impairment:

There is currently no experience of olmesartan medoxomil in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the maximum dose is 20 mg olmesartan medoxomil.

Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Therefore the use of Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg in patients with moderate and severe hepatic impairment, cholestasis and biliary obstruction is contraindicated (see sections 4.3, 5.2). Care should be taken in patients with mild impairment (see section 4.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

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

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Olmetec Plus is not recommended in such patients.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance:

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Conversely, due to antagonism at the angiotensin-II receptors (AT₁) through the olmesartan medoxomil component of Olmetec Plus, hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e.g. heparin) should be co-administered cautiously with Olmetec Plus (see section 4.5).

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium:

As with other angiotensin II receptor antagonists, the co

Ethnic differences:

As with all other angiotensin II receptor antagonist containing products, the blood pressure lowering effect of Olmetec Plus is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Anti-doping test:

Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

Pregnancy:

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other:

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

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Potential interactions related to the Olmetec Plus combination:

Concomitant use not recommended

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of Olmetec Plus and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen:

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products:

NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Concomitant use to be taken into account

Amifostine:

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents:

The blood pressure lowering effect of Olmetec Plus can be increased by concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil:

Concomitant use not recommended

Medicinal products affecting potassium levels:

Based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Olmetec Plus, monitoring of potassium plasma levels is advised.

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Co

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to hydrochlorothiazide:

Concomitant use not recommended

Medicinal products affecting potassium levels:

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the co

Concomitant use requiring caution

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 adjusted accordingly.

Cholestyramine and colestipol resins:

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

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 Olmetec Plus 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, sparfloxacin, terfenadine, vincamine IV).

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine):

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

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

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

Antidiabetic medicinal products (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Metformin:

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta-blockers and diazoxide:

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline):

The effect of pressor amines may be decreased.

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. Co

Amantadine:

Thiazides may increase the risk of adverse effects caused by amantadine.

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.

Tetracyclines:

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This interaction is probably not applicable to doxycycline.

4.6 Pregnancy And Lactation

Pregnancy

Given the effects of the individual components in this combination product on pregnancy, the use of Olmetec Plus is not recommended during the first trimester of pregnancy (see section 4.4). The use of Olmetec Plus is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Olmesartan medoxomil

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy (see sections 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 antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonists therapy 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 angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Lactation

Olmesartan medoxomil

Because no information is available regarding the use of Olmetec Plus during breast-feeding, Olmetec Plus is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Olmetec Plus during breast-feeding is not recommended. If Olmetec Plus is used during breast-feeding, doses should be kept as low as possible.

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, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.

4.8 Undesirable Effects

Fixed dose combination:

The safety of Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg was investigated in clinical trials in 3709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide.

Further adverse events reported with the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide in the lower dose strengths 20 mg/12.5 mg and 20 mg/25 mg may be potential adverse reactions with Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg.

Adverse events of potential clinical relevance of all dose strengths of the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide are listed below by System Organ Class. Frequencies are defined as: very common (

Adverse drug reactions additionally reported from post marketing experience are also listed. For all the adverse drug reactions reported from post marketing experience only, it is not possible to assign frequency and therefore they are mentioned with a “not known” frequency (cannot be estimated from the available data).

Common (	Uncommon (	Rare (	Very rare (<1/10,000)	Not known (cannot be estimated from the available data)
Metabolism and nutrition disorders
	Hyperuricaemia Hypertriglyceridaemia Hypercholesterolaemia
Nervous system disorders
Dizziness Headache	Syncope Dizziness postural Somnolence			Disturbances in consciousness (such as loss of consciousness)
Cardiac disorders
	Palpitations
Ear and labyrinth disorders
	Vertigo
Vascular disorders
	Hypotension Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
	Cough
Gastrointestinal disorders
	Diarrhoea Nausea Vomiting Dyspepsia Abdominal pain
Skin and subcutaneous tissue disorders
	Rash Eczema			Allergic conditions (such as angioneurotic oedema and urticaria)
Musculoskeletal and connective tissue disorders
	Myalgia Muscle spasm Back pain Arthralgia Pain in extremity
Renal and urinary disorders
	Haematuria			Acute renal failure
Reproductive system and breast disorders
	Erectile dysfunction
General disorders and administration site conditions
Fatigue Asthenia Oedema peripheral Chest pain	Weakness			Asthenic conditions (such as malaise)
Investigations
	Blood potassium decreased Blood potassium increased Blood calcium increased Blood urea increased Blood lipids increased Blood creatinine increased Blood glucose increased Gamma glutamyl transferase increased Alanine aminotransferase increased Aspartate aminotransferase increased	Minor increases in mean uric acid Minor increases in blood urea nitrogen Minor decreases in mean haemoglobin and haematocrit values		Abnormal renal function tests

Additional information on the individual components:

Adverse reactions previously reported with either of the individual components may be potential adverse reactions with Olmetec Plus, even if not observed in post marketing experience and clinical trials with this product.

Olmesartan medoxomil

Further adverse events reported in clinical trials with olmesartan medoxomil monotherapy in hypertension are listed by body system and ranked under headings of frequency.

Adverse drug reactions additionally reported from post marketing experience are also listed. For all the adverse drug reactions reported from post marketing experience only, it is not possible to assign frequency and therefore they are mentioned with a “not known” frequency (cannot be estimated from the available data).

Common (	Uncommon (	Rare (	Very rare (<1/10,000)	Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders :
				Thrombocytopenia
Metabolism and nutrition disorders
Increased creatine phosphokinase		Hyperkalaemia
Cardiac disorders
	Angina pectoris
Respiratory, thoracic and mediastinal disorders
Bronchitis Pharyngitis Rhinitis
Gastrointestinal disorders
Gastroenteritis
Skin and subcutaneous tissue disorders
				Pruritus Exanthema Face oedema Allergic dermatitis
Musculoskeletal and connective tissue disorders
Arthritis Skeletal pain
Renal and urinary disorders
Urinary tract infection				Renal insufficiency
General disorders and administration site conditions
Influenza-like symptoms Pain				Lethargy
Investigations
				Increased hepatic enzymes

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. A causal relationship, however, has not been established.

Hydrochlorothiazide

Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).

Further adverse reactions reported with hydrochlorothiazide monotherapy include:

Common (	Uncommon (	Rare (	Very rare (<1/10,000)	Not known (cannot be estimated from the available data)
Infections and infestations
		Sialadenitis
Blood and lymphatic system disorders
		Leucopenia Neutropenia/ Agranulocytosis Thrombocytopenia Aplastic anaemia Haemolytic anaemia Bone marrow depression
Metabolism and nutrition disorders
Hyperglycaemia Glycosuria