Nazivin®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NASIVIN®

Composition:

Active substance: oxymetazoline;

1 ml of solution contains oxymetazoline hydrochloride 0.5 mg;

Excipients: citric acid monohydrate; sodium citrate; glycerol (85 %); benzalkonium chloride solution 50 %; purified water.

Pharmaceutical form. Nasal spray, metered.

Main physicochemical properties: almost transparent solution, from colorless to slightly yellowish tint.

Pharmacotherapeutic group. Decongestants and other agents for local use in nasal cavity disorders. Sympathomimetics, single-component preparations.

ATC code R01A A05.

Pharmacological Properties

Pharmacodynamics

The active ingredient of the metered nasal spray has sympathomimetic and vasoconstrictive effects, thereby reducing mucosal edema. The medicinal product relieves nasal mucosal swelling and restores nasal breathing. This promotes restoration of aeration of the paranasal sinuses and the middle ear cavity via the unblocked Eustachian tube.

Antiviral effects of solutions containing oxymetazoline have been demonstrated in studies with virus-infected cultured cells (therapeutic approach). This mechanism of action was confirmed by inhibition of activity of viruses causing common colds, using a plaque reduction assay, determination of residual infectivity (viral titration), and the zpE inhibition test.

Anti-inflammatory and antioxidant effects of oxymetazoline have been demonstrated in various studies. The formation of lipid mediators from arachidonic acid is significantly influenced by oxymetazoline in stimulated ex vivo alveolar macrophages. In particular, oxymetazoline-induced inhibition of 5-lipoxygenase enzyme activity suppresses the formation of pro-inflammatory signaling molecules (LTB4), while simultaneously increasing the synthesis of anti-inflammatory messenger substances (PGE2, 15-HETE). Oxymetazoline also inhibits inducible nitric oxide synthase (iNOS) in long-term cultured alveolar macrophages.

Oxymetazoline significantly suppresses oxidative stress induced by carbon ultraviolet particles in primary alveolar macrophages. It also inhibits lipid peroxidation in microsomes in an iron/ascorbate system (antioxidant effect).

Immunomodulatory effects of oxymetazoline have been demonstrated in human peripheral blood mononuclear cells. In this context, oxymetazoline significantly reduces inflammation by decreasing the production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Furthermore, oxymetazoline suppresses the immunostimulatory properties of dendritic cells.

A double-blind, parallel-group comparative study involving 247 patients demonstrated faster and greater improvement in typical symptoms of acute rhinitis (nasal congestion, rhinorrhea, sneezing, general malaise) (p < 0.05), attributable to the combined vasoconstrictive, antiviral, anti-inflammatory, and antioxidant effects of oxymetazoline. Thus, treatment with 0.05% oxymetazoline nasal spray significantly reduced the duration of common colds by an average of 2 days, from 6 to 4 days, compared to physiological saline (p < 0.001).

Pharmacokinetics

The effect of oxymetazoline begins within a few seconds.

The onset of oxymetazoline's effect was measured in an open-label observational study using the 0.05% nasal spray formulation. The effect began on average within 20.6 seconds. This finding was confirmed in a double-blind, parallel-group comparative study with isotonic saline solution involving 247 patients: onset of effect was observed on average within 25 seconds.

The effect lasts up to 12 hours.

Occasionally, the amount of absorbed oxymetazoline after intranasal administration may be sufficient to produce systemic effects, for example, on the central nervous system or the cardiovascular system.

Further pharmacokinetic data from human studies are not available.

Safety Preclinical Data

Repeated-dose toxicity studies of intranasal oxymetazoline in dogs revealed no risks to human health. The in vitro bacterial mutagenicity test was negative. There are no data on carcinogenicity. No teratogenic effects were observed in rats and rabbits. Doses exceeding the therapeutic range caused embryolethal effects or fetal growth retardation. Lactation was suppressed in rats. There are no data on fertility impairment.

Preclinical studies indicate that benzalkonium chloride, depending on concentration and duration of exposure, may inhibit ciliary motility, leading to irreversible ciliary arrest, as well as histopathological changes in the nasal mucosa.

Clinical Characteristics

Indications

• Acute rhinitis.
• Allergic rhinitis.
• Spastic vasomotor rhinitis.
• To restore drainage and nasal breathing in paranasal sinusitis, as well as in eustachitis associated with rhinitis.
• To reduce swelling prior to diagnostic procedures in the nasal passages.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Dry rhinitis.
• Should not be used after transsphenoidal hypophysectomy or other surgical interventions involving the dura mater.
• Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction

Concomitant use of oxymetazoline and:

• tricyclic antidepressants;
• monoamine oxidase inhibitors of the tranycypromine type;
• agents that increase blood pressure, —

may lead to increased blood pressure. Therefore, such concomitant use should be avoided.

Special precautions for use

The medicinal product should be used only after careful assessment of benefit versus risk in the following conditions:

• elevated intraocular pressure, particularly in angle-closure glaucoma;
• severe cardiovascular disorders (e.g. ischemic heart disease) and hypertension;
• pheochromocytoma;
• metabolic disorders (e.g. hyperthyroidism, diabetes mellitus);
• benign prostatic hyperplasia;
• porphyria;
• concomitant use of monoamine oxidase inhibitors (MAOIs) and other agents that may potentially increase blood pressure.

Prolonged use and overdosage of the nasal decongestant may lead to reduced efficacy. Misuse of this product may result in:

• reactive nasal mucosal hyperemia (rebound effect);
• chronic swelling of the nasal mucosa (rhinitis medicamentosa);
• atrophy of the nasal mucosa.

The preservative benzalkonium chloride contained in Nazivin® nasal spray, metered dose, may cause swelling of the nasal mucosa, particularly with prolonged use. If such a reaction is suspected (chronically blocked nose), an alternative intranasal medicinal product without preservatives should be selected. If a preservative-free nasal product is unavailable, use of another pharmaceutical form is recommended.

Use during pregnancy or breastfeeding

Pregnancy

Data from a limited number of pregnant women exposed to this medicinal product during the first trimester do not indicate adverse reactions of oxymetazoline affecting pregnancy or the health of the fetus and newborn. Currently, adequate epidemiological data are lacking. Animal studies have shown reproductive toxicity at doses exceeding the therapeutic range.

This medicinal product should be used during pregnancy only with particular caution, taking into account the benefit-risk ratio. Exceeding the recommended dosage is not recommended, as overdosage may impair fetal blood supply.

Breastfeeding

It is unknown whether oxymetazoline passes into human breast milk. Nazivin® nasal spray, metered dose, should be used during breastfeeding only after careful assessment of the benefit-risk ratio. Exceeding the recommended dosage is not recommended, as it may reduce breast milk production.

Ability to affect reaction speed when driving or operating machinery

Nazivin® nasal spray, metered dose, has no effect or has a negligible effect on the ability to drive or operate machinery. However, after prolonged use of the medicinal product at doses exceeding the recommended ones, a general effect on the cardiovascular system cannot be excluded. In such cases, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

Adults and children aged 6 years and older

Administer 1 spray into each nostril 2–3 times daily.

The indicated single dose of the medicinal product Nazivin®, nasal spray, metered, should not be administered more than 3 times daily.

Do not use the product for more than 7 days. Do not exceed the recommended doses.

Method of Administration

The spray mechanism operates by pressing the finger rest. Before first use, remove the protective cap, hold the bottle in hand, and press the pump several times until a consistent aerosol mist is produced. Hold the spray nozzle near the entrance of the nostril and administer one spray. After use, clean the spray nozzle and, if necessary, the protective cap.

Children

Do not use the medicinal product in children under 6 years of age.

Overdose

Overdose may occur following nasal or accidental oral ingestion. The clinical picture after intoxication with imidazole derivatives may be diverse, as periods of hyperactivity may alternate with periods of depression of the central nervous, cardiovascular, and respiratory systems.

Stimulation of the central nervous system may manifest as anxiety, excitement, hallucinations, and seizures.

Depression of the central nervous system may manifest as decreased body temperature, lethargy, drowsiness, and coma.

Other symptoms may include miosis, mydriasis, fever, sweating, pallor, cyanosis, palpitations, tachycardia, bradycardia, cardiac arrhythmia, cardiac arrest, arterial hypertension, shock hypotension, nausea and vomiting, respiratory depression, and apnea, as well as psychogenic disorders.

In children, overdose often leads to predominant central nervous system effects, including seizures and coma, bradycardia, apnea, and arterial hypertension, which may follow an initial phase of hypotension.

In cases of severe overdose, intensive therapy in a hospital setting is indicated. Activated charcoal (adsorbent), sodium sulfate (laxative), or gastric lavage (in case of ingestion of large quantities of the medicinal product) should be administered immediately, as oxymetazoline may be rapidly absorbed. Vasopressor agents are contraindicated. Non-selective α-blockers may be used as antidotes. If necessary, anticonvulsant therapy, lung ventilation, and measures to reduce body temperature should be implemented.

Side effects

The frequency of adverse reactions is classified as follows:

Very common (≥ 1/10).

Common (≥ 1/100 to < 1/10).

Uncommon (≥ 1/1,000 to < 1/100).

Rare (≥ 1/10,000 to < 1/1,000).

Very rare (< 1/10,000).

Not known (cannot be estimated from the available data).

Nervous system disorders:

Very rare: restlessness, insomnia, fatigue (drowsiness, sedative effect), headache, hallucinations (especially in children).

Cardiovascular system disorders:

Rare: palpitations, tachycardia, arterial hypertension.

Very rare: arrhythmias.

Respiratory, thoracic and mediastinal disorders:

Common: burning sensation and dryness of nasal mucosa, sneezing.

Uncommon: rebound congestion, increased swelling of the mucous membrane, epistaxis after discontinuation of use.

Very rare: apnea in infants and newborns.

Musculoskeletal and connective tissue disorders:

Very rare: convulsions (mainly in children).

Immune system disorders:

Uncommon: hypersensitivity reactions (angioedema, rash, pruritus).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life: 3 years.

After first opening of the bottle, do not store for more than 6 months.

Storage conditions: Store at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging: 10 ml in a bottle with a dosing device, 1 bottle in a cardboard box. The bottle contains at least 143 sprays.

Classification for supply: Over-the-counter.

Manufacturer:

1. Sofarimex – Indústria Química e Farmacêutica, S.A.

2. Procter & Gamble Manufacturing GmbH

Manufacturer's address and place of business:

1. Av. das Indústrias - Alto do Colaride, Cacém, 2735-213, Portugal.

2. Procter & Gamble Strasse 1, 64521 Groß-Gerau, Hesse, Germany.