Pivalone Tixocortol Pivalate Nasal Suspension

CAREFULLY SHAKE THE BOTTLE BEFORE USE

COMPOSITION Tixocortol pivalate…………………………………………………………………… 1.000 g N-cetylpyridinium chloride……………………………………………………………0.020 g Excipient to………………………………………………………………………………100 g

Bottle containing 10 ml of suspension.

PHARMACEUTICAL FORM 1% tixocortol pivalate nasal suspension (10 ml nasal spray bottle)

THERAPEUTIC PROPERTIES Tixocortol pivalate: local anti-inflammatory corticoid devoid of systemic effects.

INDICATIONS Allergic rhinitis Seasonal rhinitis Acute congestive rhinitis Chronic congestive rhinitis Vasomotor rhinitis

CONTRAINDICATIONS Antecedent allergy to the product. Epistaxis Existence of viral or fungal infections during treatment and existence of significant local superinfection

DOSAGE AND ADMINISTRATION 1 to 2 pulverizations in each nostril 2 to 4 times a day. Do not exceed the prescribed dose.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE To be used after carefully blowing or cleaning the nose.

In the event of systemic signs of bacterial infection, treatment with a systemic antibiotic must be considered.

Events of epidural lipomatosis, central serous chorioretinopathy and pheochromocytoma crisis have been associated with systemic administration of corticosteroids. Long-term administration of inhaled or topical corticosteroid formulations may also be associated with these potential systemic effects.

Page 1 of 6 Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES This medication would not be expected to impair the ability to drive or use machines.

SIDE EFFECTS ADRs by SOC and CIOMS frequency category listed in order of decreasing medical seriousness within each frequency category and SOC System Very Common Uncommon Rare Very Frequency Organ Class Common ≥1/100 ≥1/1,000 to ≥ Rare Not Known ≥1/10 to <1/10 <1/100 1/10,000 <1/10,0 (cannot be to 00 estimated <1/1,000 from the available data)

Immune Hypersensitivity* system disorders Respiratory, Nasal dryness*, thoracic and Rhinalgia†, mediastinal Epistaxis disorders Skin and Angioedema* subcutaneous tissue disorders Eye disorder Vision, blurred (see section Special Warnings and Precautions for Use) General Face oedema* disorders and administration site conditions * These reactions regress at discontinuation of the treatment. † May occur at the start of treatment.

FERTILITY, PREGNANCY AND LACTATION In an oral fertility and developmental toxicity study in rats, there was no effect on fertility and tixocortol was not teratogenic, although it was shown to be teratogenic in a study in rabbits (see section Preclinical safety data).

Since adequate human reproductive studies have not been done with tixocortol, this medicinal product should be used during pregnancy only after a careful assessment of the benefit risk ratio to the mother and fetus/child. Avoid using the product during pregnancy unless potential benefit outweighs risk.

Page 2 of 6 It is not known whether the drug is excreted in human milk. Breast-feeding should be avoided during treatment.

OVERDOSE No cases of tixocortol overdose are currently known.

ABUSE AND DEPENDENCE Tixocortol has not shown the potential for drug abuse or dependence.

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Local corticosteroid: anti-allergic, anti-inflammatory.

Tixocortol pivalate has the local efficacy of reference corticosteroids but is devoid of significant corticosteroid activity remote from the site of application in humans.

Administration of 130 times the daily therapeutic dose in humans does not lead to any systemic glucocorticoid effects.

The PIVALONE 1% nasal suspension dosage form respects nasal drainage by the ciliary beats of the pituitary mucous membranes.

Pharmacokinetic properties Studies conducted in animals and humans have demonstrated the extremely rapid metabolism of tixocortol pivalate, explaining the absence of any significant systemic corticosteroid effects in humans.

Tixocortol pivalate is well absorbed by the oral route; however, even after oral administration of a very large dose (2 g), only inactive metabolites, devoid of any glucocorticoid action, are found in the general circulation. This is due to extremely rapid degradation of tixocortol pivalate, mainly hepatic.

Preclinical safety data General toxicity studies in rats and nonhuman primates did not identify any special hazards.

In an oral fertility and developmental toxicity study in rats, there was no effect on fertility. Prenatal developmental toxicity consisted of slight increases in post implantation loss and reduced fetal weight, and tixocortol was not teratogenic. There were no adverse effects on postnatal development.

In an embryo fetal development study, tixocortol pivalate was administered daily via oral gavage to timed pregnant rabbits at doses up to 360 mg/kg/day from gestation day 6 through 18. At doses ≥120 mg/kg/day, at which maternal toxicity was observed, there were reduced fetal body weights and increases in the incidence of major malformations (hydrocephaly, cleft palate, and skeletal malformations). Increased post implantation loss, lower litter sizes, and skeletal anomalies were also observed at 360 mg/kg/day. On a mg/kg basis, the doses administered in this study greatly exceeded those in humans receiving the topically administered product.

Page 3 of 6 Tixocortol was not clastogenic in human lymphocytes and a negative response was obtained in the in vivo micronucleus assay in mice. Tixocortol did not show any carcinogenic potential in 2-year oral gavage studies in rats dosed up to 250 mg/kg/day and in mice dosed up to 100 mg/kg/day.

INCOMPATIBILITIES AND INTERACTIONS No known incompatibilities and drugs interactions have been reported.

STORAGE AND STABILITY Shelf-life: 3 years Store at or below 30°C

NATURE AND CONTENTS OF CONTAINER Plastic spray bottles

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING No special requirements.

Page 4 of 6 HOW TO USE 1. Carefully shake the bottle. Remove the protective cap.

2. Press several times to start the pulverization process.

3. Insert the long end of the bottle vertically into the nostril and press firmly.

PRODUCT OWNER Pfizer Inc. 235 East 42nd Street

Page 5 of 6 New York 10017, US

PIV-SIN-0919/0 Date of Last Revision: September 2019

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