SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

RINATEC 21 micrograms per metered dose, Nasal Spray solution.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

RINATEC is an aqueous formulation (adjusted to pH 4.0 - 5.0) available as a 15 ml (180 metered doses) and 30 ml (380 metered doses) pump spray.

Each valve actuation delivers 70 pl of solution containing 21 micrograms of ipratropium bromide.

3.    PHARMACEUTICAL FORM

Nasal Spray, solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

RINATEC is indicated for the symptomatic relief of rhinorrhoea in allergic and nonallergic rhinitis.

4.2 Posology and method of administration

Adults: Two sprays (42 pg) in each nostril administered 2 - 3 times a day.

Children:The use of RINATEC has not been evaluated in children, and therefore is not recommended for use in patients below the age of 12 years.

To obtain the best results from your nasal spray follow the simple instructions given below. If you are unclear about how to use the nasal spray ask your doctor or pharmacist to explain.

1.Remove the dust cap.

2.The nasal spray pump must be primed before RINATEC is used for the first time.

To prime the pump, hold the bottle with your thumb at the base and your index and middle fingers on the white shoulder area. Make sure the bottle points upright and away from your eyes. Press your thumb firmly and quickly against the bottle seven times. The pump is now primed and can be used. Your pump will hold its prime for up to 24 hours. If you have not used your pump for more than 24 hours, you will need to prime it again before use. Reprime the pump as before, but this time only two sprays are required. If you have not used your pump for more than 7 days reprime using 7 sprays.

3.Blow your nose to clear your nostrils if necessary.

4.Close one nostril by gently placing your fingers against the side of your nose. Tilt your head slightly forward and, keeping the bottle upright, insert the nasal tip into the other nostril. Point the tip toward the back and outer side of the nose.

Press firmly and quickly upwards with the thumb at the base while holding the white shoulder portion of the pump between your index and middle fingers. Following each spray, sniff deeply and breathe out through the mouth.

After spraying the nostril and removing the unit, tilt your head backwards for a few seconds to let the spray spread over the back of the nose.

5.Repeat step 4 in the other nostril.

6.Replace the cap.

Avoid spraying RINATEC in or around your eye. Should this occur, immediately flush your eye with cold tap water for several minutes. If you accidently spray RINATEC in your eyes, you may experience a temporary blurring of vision and increased sensitivity to light, which may last a few hours. Follow your doctor’s instructions about when and how to take your medicine and always read the label.

If the nasal tip becomes clogged, remove the clear plastic dust cap. Hold the nasal tip under warm running water for about a minute. Dry the nasal tip, reprime the nasal spray pump and replace the plastic dust cap.

4.3 Contraindications

RINATEC is contraindicated in patients known to be hypersensitive to atropine or its derivatives or to any other component of the product.

4.4 Special warnings and precautions for use

Immediate hypersensitivity reactions following the use of RINATEC have been demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-outflow obstruction).

As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, RINATEC, as with other anticholinergics, should be used with caution in these patients.

There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic beta₂-agonist, has come into contact with the eyes. Thus, patients must be instructed in the correct administration of RINATEC.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

RINATEC contains the (antimicrobial) preservative benzalkonium chloride which may cause irritation of the nasal mucosa.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of RINATEC with other drugs commonly prescribed for perennial rhinitis i.e. antihistamines, decongestants or nasal steroids does not increase the incidence of nasal or non-nasal side-effects.

Ipratropium bromide is minimally absorbed into the systemic circulation; nonetheless, there is some potential for additive interaction with other concomitantly administered

anticholinergic medications, including ipratropium bromide-containing aerosols for oral inhalation.

4.6 Fertility, pregnancy and lactation

The safety of RINATEC during human pregnancy has not been established. The benefits of using RINATEC during a confirmed or suspected pregnancy must be weighed against the possible hazards to the unborn child. Preclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.

It is not known whether ipratropium bromide is excreted into breast milk. It is unlikely that ipratropium bromide would reach the infant to an important extent, however caution should be exercised when RINATEC is administered to nursing mothers.

Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility (see section 5.3). Clinical data on fertility are not available for ipratropium bromide.

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, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with Rinatec. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Many of the listed undesirable effects can be assigned to the anticholinergic properties of RINATEC. As with all topical therapy RINATEC may show symptoms of local irritation. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.

The most frequent side effects reported in clinical trials were epistaxis, nasal dryness, headache, nasal discomfort and throat irritation

> 1/10

> 1/100 < 1/10 > 1/1,000< 1/100 > 1/10,000 < 1/1,000 < 1/10,000

⁽¹⁾    ocular complications have been reported when aerolised ipratropium

bromide, either    alone or in combination with an adrenergic beta₂-

agonist, has come into contact with the    eyes- see section 4.4.

⁽²⁾    the risk of urinary retention may be increased in patients with pre-existing

urinary    outflow tract obstruction

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9. Overdose

No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of RINATEC, no serious anticholinergic symptoms are to be expected. As with other anticholinergics, dry mouth, visual accommodation disturbances and tachycardia would be the expected symptoms and signs of overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Ipratropium bromide, a quaternary ammonium derivative of atropine is an anticholinergic drug. Ipratropium bromide administered intranasally has a localised parasympathetic blocking action, which reduces watery hypersecretion from mucosal glands in the nose.

5.2 Pharmacokinetic Properties

Absorption

Ipratropium is a quaternary amine that is rapidly absorbed from the nasal mucosa, however to a low extent. In healthy volunteers approximately 10% of a nasally given dose was excreted unchanged in the urine over 24 hours.

Distribution

The drug is minimally (less than 20%) bound to plasma proteins. The quarternary amine of the ipratropium ion does not cross the blood-brain barrier.

Biotransformation

Ipratropium has a mean total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of the dose is mainly metabolised by conjugation (40%), wheras after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).

Elimination

The half-life of the terminal elimination phase is approximately 1.6 hours.

In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation.

Therefore the dominant excretion of drug-related radioactivity occurs via the kidneys. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.

5.3 Preclinical safety data

The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order: intravenous > subcutaneous > oral > inhalation > intranasal.

Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for RINATEC. Results of various mutagenicity tests were negative.

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral dose levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the fetal weight was reduced. Treatment-related malformations were not observed. The highest, technically feasible doses for inhalation of the metered dose aerosol, 1.5 mg/kg/day in rats (human equivalent dose (HED) of 0.24 mg/kg) and 1.8 mg/kg/day in rabbits (HED of 0.576 mg/kg), showed no adverse effects on reproduction.

The maximum recommended human daily dose (MRHDD) of Rinatec Nasal Spray (0.03%) is 2 sprays in each nostril (= 42 mcg/nostril) up to 3-times a day, or 0.136 mg. This equals to a dose of 0.00272 mg/kg, based on a body weight of 50 kg. This MRHDD based on mg/kg is 88- and 211-fold less than the highest, technically feasible doses tested in rats and rabbits, respectively which showed no adverse effects on reproduction.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium chloride

Benzalkonium chloride Disodium edetate Purified water

Hydrochloric acid and sodium hydroxide are used for pH adjustment.

6.2.    Incompatibilities

None known.

6.3.    Shelf life

2 years.

In-use: 6 months.

6.4.    Special precautions for storage

Do not store above 25 °C.

6.5    Nature and contents of container

RINATEC is a clear colourless aqueous solution adjusted to the optimum pH 4.0-5.0. The solution is filled into either 15 ml or 30 ml amber glass bottles (Type I glass) fitted with 70pL manually activated nasal pump/closures.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS