Cyprostat 100mg

1. Name Of The Medicinal Product

Cyprostat® 100mg

2. Qualitative And Quantitative Composition

Each white, scored tablet contains 100mg cyproterone acetate.

Excipient: lactose 184.3 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Management of patients with prostatic cancer (1) to suppress "flare" with initial LHRH analogue therapy,(2) in long-term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred, and (3) in the treatment of hot flushes in patients under treatment with LHRH analogues or who have had orchidectomy.

4.2 Posology And Method Of Administration

Adults

Method of admininstration

For oral administration.

Dosage regimen

The maximum daily dose is 300 mg.

For long-term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred the dosage is 200-300 mg/day.

Dosage for suppression of "flare" with initial LHRH analogue therapy:

Initially 1 tablet of Cyprostat 100mg twice daily (200mg) alone for 5 - 7 days, followed by 1 tablet of Cyprostat 100mg twice daily (200mg) for 3 – 4 weeks together with the LHRH analogue therapy in the dosage recommended by the marketing authorisation holder (see SmPC of LHRH analogue).

For the above two indications the dosage should be divided into 2 - 3 doses per day and taken with some liquid after meals.

For the treatment of hot flushes in patients under treatment with LHRH analogues or who have had orchidectomy a 50 mg starting dose, with upward titration if necessary within the range 50-150 mg/day, is recommended. For this indication the dosage should be divided into 1 - 3 doses per day and taken with some liquid after meals.

Additional information on special populations

Children and adolescents: Cyprostat is not recommended for use in male children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

Cyprostat must not be given before the conclusion of puberty since an unfavourable influence on longitudinal growth and the still unstabilised axes of endocrine function cannot be ruled out.

Elderly patients:

There are no data suggesting the need for a dosage adjustment in elderly patients.

Patients with hepatic impairment:

The use of Cyprostat is contraindicated in patients with liver diseases (see section 4.4 and 4.8).

Patients with renal impairment:

The use of Cyprostat in patients with renal impairment has not been investigated. There are no data suggesting the need for dosage adjustment in patients with renal impairment (see section 5.2).

4.3 Contraindications

Cyprostat must not be used in patients with:

Meningioma or a history of meningioma.

Liver diseases (including Dubin-Johnson syndrome and Rotor syndrome)

Malignant tumours (except for carcinoma of the prostate)

Previous or existing liver tumours (only if these are not due to metastases from carcinoma of the prostate)

Wasting diseases (with the exception of inoperable carcinoma of the prostate)

Existing thromboembolic processes

Hypersensitivity to the active substance or any of the excipients.

4.4 Special Warnings And Precautions For Use

Liver: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, has been observed in patients treated with Cyprostat. At dosages of 100 mg and above cases with fatal outcome have also been reported. Most reported fatal cases were in men with advanced prostatic cancer. Toxicity is dose-related and develops, usually, several months after treatment has begun. Liver function tests should be performed pre-treatment, regularly during treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, Cyprostat should be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case Cyprostat should be continued only if the perceived benefit outweighs the risk.

In very rare cases benign and malignant liver tumours, which may lead to life-threatening intra-abdominal haemorrhage, have been observed after the use of Cyprostat. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.

Thromboembolic events: The occurrence of thromboembolic events has been reported in patients using Cyprostat, although a causal relationship has not been established. Patients with previous arterial or venous thrombotic / thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction), with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events, and may be at risk of recurrence of the disease during Cyprostat therapy.

In patients with a history of thromboembolic processes or suffering from sickle-cell anaemia or severe diabetes with vascular changes, the risk: benefit ratio must be considered carefully in each individual case before Cyprostat is prescribed.

Meningiomas:

The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above. If a patient treated with Cyprostat is diagnosed with meningioma, treatment with Cyprostat must be stopped (see section 4.3).

Chronic depression: It has been found that some patients with severe chronic depression deteriorate whilst taking Cyprostat therapy. Such patients should be closely monitored for signs of deterioration and warned to contact their doctor immediately if their depression worsens.

Shortness of breath: Shortness of breath may occur under high-dosed treatment with Cyprostat. This may be due to the stimulatory effect of progesterone and synthetic progestogens on breathing, which is accompanied by hypocapnia and compensatory alkalosis, and which is not considered to require treatment.

Adrenocortical function: During treatment, adrenocortical function should be checked regularly, as preclinical data suggest a possible suppression due to the coricoid-like effect of Cyprostat with high doses (see section 5.3).

Diabetes mellitus: Strict medical supervision is necessary if the patient suffers from diabetes as Cyprostat can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment because the requirement for oral antidiabetics or insulin can change. See also section 4.5.

Anaemia: Anaemia has been reported during long-term treatment. Therefore, the red blood cell count should be checked regularly during treatment.

Lactose: Cyprostat contains 184.3 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Patients who are on a lactose-free diet should take this amount into consideration.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Diabetes: At high therapeutic cyproterone acetate doses of three times 100mg per day, cyproterone acetate may inhibit CYP2C8 (see below). Thiazolidinediones (i.e. the anti-diabetics pioglitazone and rosiglitazone) are substrates of CYP2C8 (increased blood levels of these anti-diabetics may require dose adjustment).

Other interactions: Clinical interaction studies have not been performed. However, since cyproterone acetate is metabolised by CYP3A4, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate. On the other hand, inducers of CYP3A4 such as rifampicin, phenytoin and products containing St. John's wort may reduce the levels of cyproterone acetate.

Based on in vitro inhibition studies, an inhibition of the cytochrome P450 enzymes CYP2C8, 2C9, 2C19, 3A4 and 2D6 is possible at high cyproterone acetate doses of 100 mg three times per day.

The risk of statin-associated myopathy or rhabdomyolysis may be increased when those HMG-CoA inhibitors (statins) which are primarily metabolised by CYP3A4 are co-administered with high therapeutic cyproterone acetate doses, since they share the same metabolic pathway.

4.6 Pregnancy And Lactation

Not applicable

4.7 Effects On Ability To Drive And Use Machines

Fatigue and lassitude are common - patients should be warned about this and if affected should not drive or operate machinery.

4.8 Undesirable Effects

The most frequently observed adverse drug reactions (ADRs) in patients receiving Cyprostat are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.

The most serious ADRs in patients receiving Cyprostat are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage and thromboembolic events.

The following approximate incidences were estimated from published reports of a number of small clinical trials and spontaneous ADR reports:

- very common: incidence

- common: incidence < 1:10 but

- uncommon: incidence < 1:100 but

- rare: incidence < 1:1000 but

- very rare: incidence <1:10,000

- not known (cannot be estimated from available data)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare:	Benign and malignant liver tumours which may lead to life-threatening intra-abdominal haemorrhage (see section 4.4).
Not known:	The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above.
Blood and the lymphatic system disorders
Not known:	Anaemia during long-term treatment (see section 4.4).
Immune system disorders
Rare:	Hypersensitivity reactions.
Endocrine disorders
Not known:	Suppression of adrenocortical function.
Metabolism and nutrition disorders
Common:	Changes in bodyweight during long term treatment (chiefly weight gains in association with fluid retention).
Psychiatric disorders
Common:	Depressive moods and restlessness (temporary).
Vascular disorders
Not known:	Thromboembolic events, although a causal relationship has not been established (see section 4.4).
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea (see section 4.4).
Hepato-biliary disorders
Common:	Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure has been observed in patients treated with Cyprostat. At dosages of 100 mg and above, cases with fatal outcome have also been reported. Most reported fatal cases were in men with advanced carcinoma of the prostate. Toxicity is dose related and develops, usually, several months after treatment has begun.
Skin and subcutaneous tissue disorders
Uncommon:	Rash
Not known:	Reduction of sebum production leading to dryness of the skin and improvement of existing acne vulgaris has been reported as well as; transient patchy loss and reduced growth of body hair, increased growth of scalp hair, lightening of hair colour and female type of pubic hair growth.
Musculoskeletal and connective tissue disorders
Not known:	Osteoporosis (due to long-term androgen deprivation).
Reproductive system disorders
Very common:	Decreased libido, erectile dysfunction, reduced sexual drive and inhibition of gonadal function. These changes are reversible after discontinuation of therapy.
Inhibition of spermatogenesis:
Very common:	Sperm count and the volume of ejaculate are reduced.
Infertility is usual, and there may be azoospermia after 8 weeks. There is usually slight atrophy of the seminiferous tubules. Follow-up examinations have shown these changes to be reversible, spermatogenesis usually reverting to its previous state about 3-5 months after stopping Cyprostat, or in some users, up to 20 months. That spermatogenesis can recover even after very long treatment is not yet known. There is evidence that abnormal sperms which might give rise to malformed embryos are produced during treatment with Cyprostat.
Gynaecomastia:
Common:	Gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation.
Rare:	Galactorrhoea and tender benign nodules.
Symptoms mostly subside after discontinuation of treatment or reduction of dosage.
General disorders and administration site conditions
Common:	Hot flushes, sweating, fatigue and lassitude.

4.9 Overdose

There have been no reports of ill-effects of overdosage, which it is, therefore, generally unnecessary to treat. There are no specific antidotes and if treatment is required it should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Prostatic carcinoma and its metastases are in general androgen-dependent. Cyproterone acetate exerts a direct anti-androgen action on the tumour and its metastases. It also has progestogenic activity, which exerts a negative feedback effect on the hypothalamic receptors, so leading to a reduction in gonadotrophin release, and hence to diminished production of testicular androgens. Sexual drive and potency are reduced and gonadal function is inhibited.

The antigonadotropic effect of cyproterone acetate is also exerted when administered with LHRH analogues. The initial increase of testosterone caused by this class of substances is reduced by cyproterone acetate.

An occasional tendency for the prolactin levels to increase slightly has been observed under higher doses of cyproterone acetate.

5.2 Pharmacokinetic Properties

Following oral administration, cyproterone acetate is completely absorbed over a wide dose range. The ingestion of 100 mg of cyproterone acetate gives maximum serum levels of about 239 ng/ml at about 3 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 h, with a terminal half-life of 42.8 ± 9.7 h.. The total clearance of cyproterone acetate from serum is 3.8 ± 2.2 ml/min/kg. Cyproterone acetate is metabolised by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15ß-hydroxy derivative.

Some drug is excreted unchanged with bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion proceeds with a half-life of 1.9 days. Metabolites from plasma are eliminated at a similar rate (half-life of 1.7 days).

Cyproterone acetate is almost exclusively bound to plasma albumin. About 3.5 - 4 % of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.

The absolute bioavailability of cyproterone acetate is almost complete (88 % of dose).

5.3 Preclinical Safety Data

Systemic toxicity

Preclinical data reveal no specific risk for humans based on conventional studies of repeated dose toxicity beyond those discussed in other sections of the SPC.

Experimental investigations produced corticoid-like effects on the adrenal glands in rats and dogs following higher dosages, which could indicate similar effects in humans at the highest given dose (300 mg/day).

Genotoxicity and carcinogenicity

Recognised first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, the DNA-adduct level in the dog liver cells was extremely low.

This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly preneoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutation. The clinical relevance of these findings is presently uncertain.

In long-term carcinogenicity studies in rats cyproterone acetate increased the incidence of liver tumours including carcinomas at high doses which concomitantly caused liver toxicity and exceeded the maximum human dose. Further investigations into rodents at lower, non-hepatotoxic doses revealed benign liver proliferations similar to effects described for other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Povidone 25 000

Magnesium stearate (E572)

Lactose

6.2 Incompatibilities

None known

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

Cartons containing PVC film and aluminium foil blister packs of 42 or 84 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

Trading as: Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0524

9. Date Of First Authorisation/Renewal Of The Authorisation

01 May 2008

10. Date Of Revision Of The Text

26 January 2011

Calcichew-D3 500 mg / 400IU Caplets

1. Name Of The Medicinal Product

Calcichew-D₃ 500 mg/400 IU Caplets

2. Qualitative And Quantitative Composition

One tablet contains:

Calcium carbonate equivalent to 500 mg calcium

Cholecalciferol concentrate (powder form) equivalent to 400 IU (10 microgram ) cholecalciferol (vitamin D₃)

Excipient(s):

Sorbitol (E420), 154 mg

Sucrose, 1.6 mg

Soya-bean oil, hydrogenated, 0.33 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Oval, white/off white, film-coated tablets. May have hardly visible grey spots.

4. Clinical Particulars

4.1 Therapeutic Indications

Prevention and treatment of vitamin D and calcium deficiency in the elderly.

Vitamin D and calcium supplement as an adjunct to specific osteoporosis treatment of patients who are at risk of vitamin D and calcium deficiency.

4.2 Posology And Method Of Administration

Adults and elderly

One film-coated tablet twice daily. The tablet may be swallowed or chewed.

Dosage in hepatic impairment

No dose adjustment is required

Dosage in renal impairment

Calcichew-D₃ 500 mg/400 IU Caplets should not be used in patients with severe renal impairment.

Calcichew-D₃ 500 mg/400 IU Caplets are not intended for use in children.

4.3 Contraindications

Diseases and/or conditions resulting in hypercalcaemia and/or hypercalcuria

Severe renal impairment

Nephrolithiasis

Hypervitaminosis D

Hypersensitivity to soya or peanut

Hypersensitivity to the active substances or to any of the excipients

4.4 Special Warnings And Precautions For Use

During long-term treatment, serum calcium levels should be followed and renal function should be monitored through measurements of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics (see section 4.5) and in patients with a high tendency to calculus formation. In case of hypercalcaemia or signs of impaired renal function the dose should be reduced or the treatment discontinued.

Vitamin D should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not metabolised normally and other forms of vitamin D should be used (see section 4.3, contraindications).

Calcichew-D₃ 500 mg/400 IU Caplets should be prescribed with caution to patients suffering from sarcoidosis, due to the risk of increased metabolism of vitamin D into its active form. These patients should be monitored with regard to the calcium content in serum and urine.

Calcichew-D₃ 500 mg/400 IU Caplets should be used cautiously in immobilised patients with osteoporosis due to increased risk of hypercalcaemia.

The content of vitamin D (400 IU) in Calcichew-D₃ 500 mg/400 IU Caplets should be considered when prescribing other medicinal products containing vitamin D. Additional doses of calcium or vitamin D should be taken under close medical supervision. In such cases it is necessary to monitor serum calcium levels and urinary calcium excretion frequently.

Co-administration with tetracyclines or quinolones is usually not recommended, or must be done with precaution (see section 4.5).

Calcichew-D₃ 500 mg/400 IU Caplets contains sorbitol (E420) and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide diuretics.

Calcium carbonate may interfere with the absorption of concomitantly administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium.

Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium and vitamin D. Patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.

If a bisphosphonate is used concomitantly, this preparation should be administered at least one hour before the intake of Calcichew-D₃ 500 mg/400 IU Caplets since gastrointestinal absorption may be reduced.

The efficacy of levothyroxine can be reduced by the concurrent use of calcium, due to decreased levothyroxine absorption. Administration of calcium and levothyroxine should be separated by at least four hours.

The absorption of quinolone antibiotics may be impaired if administered concomitantly with calcium. Quinolone antibiotics should be taken two hours before or six hours after intake of calcium.

4.6 Pregnancy And Lactation

Pregnancy

During pregnancy the daily intake should not exceed 1500 mg calcium and 600 IU vitamin D. Studies in animals have shown reproductive toxicity of high doses of vitamin D. In pregnant women, overdoses of calcium and vitamin D should be avoided as permanent hypercalcaemia has been related to adverse effects on the developing foetus. There are no indications that vitamin D at therapeutic doses is teratogenic in humans. Calcichew-D₃ 500 mg/400 IU Caplets can be used during pregnancy, in case of a calcium and vitamin D deficiency.

Breast-feeding

Calcichew-D₃ 500 mg/400 IU Caplets can be used during breast-feeding. Calcium and vitamin D₃ pass into breast milk. This should be considered when giving additional vitamin D to the child.

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. An effect is however, unlikely.

4.8 Undesirable Effects

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: uncommon (

Metabolism and nutrition disorders

Uncommon: Hypercalcaemia and hypercalciuria.

Gastrointestinal disorders

Rare: Constipation, flatulence, nausea, abdominal pain, and diarrhoea.

Very rare: Dyspepsia

Skin and subcutaneous tissue disorders

Very rare: Pruritus, rash and urticaria.

4.9 Overdose

Overdose can lead to hypervitaminosis and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polidipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.

Treatment of hypercalcaemia: The treatment with calcium and vitamin D must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides must also be discontinued. Emptying of the stomach in patients with impaired consciousness. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and CVP should be followed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Calcium, combination with other drugs

ATC code: A12AX

Vitamin D increases the intestinal absorption of calcium.

Administration of calcium and vitamin D₃ counteracts the increase of parathyroid hormone (PTH) which is caused by calcium deficiency and which causes increased bone resorption.

A clinical study of institutionalised patients suffering from vitamin D deficiency indicated that a daily intake of two calcium and vitamin D₃ 500 mg/400 IU chewable tablets for six months normalised the value of the 25-hydroxylated metabolite of vitamin D₃ and reduced secondary hyperparathyroidism and alkaline phosphatases.

An 18 month double-blind, placebo controlled study including 3270 institutionalised women aged 84+/- 6 years who received supplementation of vitamin D (800 IU/day) and calcium phosphate (corresponding to 1200 mg/day of elemental calcium), showed a significant decrease of PTH secretion. After 18 months, an "intent-to treat" analysis showed 80 hip fractures in the calcium-vitamin D group and 110 hip fractures in the placebo group (p=0,004). A follow-up study after 36 months showed 137 women with at least one hip fracture in the calcium-vitamin D group (n=1176) and 178 in the placebo group (n=1127) (p<0,02).

5.2 Pharmacokinetic Properties

Calcium

Absorption: The amount of calcium absorbed through the gastrointestinal tract is approximately 30% of the swallowed dose.

Distribution and metabolism: 99% of the calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood-calcium content is in the physiologically active ionised form with approximately 10% being complexed to citrate, phosphate or other anions, the remaining 40% being bound to proteins, principally albumin.

Elimination: Calcium is eliminated through faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.

Vitamin D

Absorption: Vitamin D is easily absorbed in the small intestine.

Distribution and metabolism: Cholecalciferol and its metabolites circulate in the blood bound to a specific globulin. Cholecalciferol is converted in the liver by hydroxylation to 25-hydroxycholecalciferol. It is then further converted in the kidneys to the active form 1,25 dihydroxycholecalciferol. 1,25 dihydroxycholecalciferol is the metabolite responsible for increasing calcium absorption. Vitamin D which is not metabolised is stored in adipose and muscle tissues.

Elimination: Vitamin D is excreted in faeces and urine.

5.3 Preclinical Safety Data

At doses far higher than the human therapeutic range teratogenicity has been observed in animal studies. There is further no information of relevance to the safety assessment in addition to what is stated in other parts of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Sorbitol (E420)

Mannitol

Acesulfame potassium

Flavouring (lemon)

Croscarmellose sodium

Cellulose, microcrystalline

Magnesium stearate

Maltodextrin

Tocopherol-rich extract

All-rac-alpha-tocopherol

Soya-bean oil, hydrogenated

Gelatin

Sucrose

Maize starch

Film-coating:

Talc

Hypromellose

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the container tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

The Caplets are packed in:

HDPE containers with HDPE screw caps: 100 tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Shire Pharmaceuticals Limited

Hampshire International Business Park

Chineham, Basingstoke,

RG24 8EP

8. Marketing Authorisation Number(S)

PL 08557/0057

9. Date Of First Authorisation/Renewal Of The Authorisation

2008/06/04

10. Date Of Revision Of The Text

08-Jun-2011

Econopred Plus Drops

Pronunciation: pred-NISS-oh-lone ASS-uh-tate
Generic Name: Prednisolone Acetate
Brand Name: Omnipred and Pred Forte

Econopred Plus Drops are used for:

Treating inflammation of the eyes and eyelids due to certain conditions. It may also be used for other conditions as determined by your doctor.

Econopred Plus Drops are an ophthalmic corticosteroid. Exactly how Econopred Plus Drops works is not known.

Do NOT use Econopred Plus Drops if:

• you are allergic to any ingredient in Econopred Plus Drops or to other corticosteroids (eg, prednisone)


• you have certain eye infections (eg, herpes, tuberculosis, fungal, or viral infections), chickenpox, or an infection due to smallpox vaccination (vaccinia)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Econopred Plus Drops:

Some medical conditions may interact with Econopred Plus Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have diabetes, glaucoma, optic nerve damage, or thinning of the cornea or other eye tissues

Some MEDICINES MAY INTERACT with Econopred Plus Drops. Because little, if any, of Econopred Plus Drops are absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Econopred Plus Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Econopred Plus Drops:

Use Econopred Plus Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Shake well before each use.


• To use Econopred Plus Drops in the eye, first, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eyelid for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean, dry tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them.


• To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including the eye. Keep the container tightly closed.


• If your doctor prescribed more than 1 eye medicine, ask the best order for using each medicine.


• Do not wear contact lenses while you are using Econopred Plus Drops. Take care of your contact lenses as directed by the manufacturer. Check with your doctor before you use them.


• If you miss a dose of Econopred Plus Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Econopred Plus Drops.

Important safety information:

• Econopred Plus Drops may cause blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Econopred Plus Drops with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Some of these products contain sulfites. Sulfites may cause an allergic reaction in some patients (eg, asthma patients). If you have ever had an allergic reaction to sulfites, ask your pharmacist if your product has sulfites in it.


• Do NOT use more than the recommended dose or use for future eye problems without checking with your doctor.


• Lab tests, including eye exams, may be performed while you use Econopred Plus Drops. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Econopred Plus Drops should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Econopred Plus Drops while you are pregnant. It is not known if Econopred Plus Drops are found in breast milk. Do not breast-feed while taking Econopred Plus Drops.

Possible side effects of Econopred Plus Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Blurred vision; temporary burning or stinging.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in vision; continued or worsening itching, swelling, or irritation; continuing blurred vision; discharge from eyes; eye pain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Econopred Plus side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Econopred Plus Drops:

Store Econopred Plus Drops at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not freeze. Do not store in the bathroom. Keep Econopred Plus Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Econopred Plus Drops, please talk with your doctor, pharmacist, or other health care provider.


• Econopred Plus Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Econopred Plus Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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• Econopred Plus Side Effects (in more detail)
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Julab

Julab may be available in the countries listed below.

Ingredient matches for Julab

Selegiline

Selegiline hydrochloride (a derivative of Selegiline) is reported as an ingredient of Julab in the following countries:

• Hong Kong

International Drug Name Search

Prevident 5000 Booster

sodium fluoride

Dosage Form: gel, dentifrice
Colgate®

PreviDent®5000 ppm

BOOSTER

Rx ONLY

1.1% Sodium Fluoride

Prescription Strength Toothpaste

Prevident 5000 Booster Description

Self-topical neutral fluoride toothpaste containing 1.1% (w/w) sodium fluoride for use as a dental caries preventive in adults and pediatric patients.

Active Ingredient

Sodium fluoride 1.1% (w/w)

Inactive Ingredients

water, sorbitol, hydrated silica, PEG-12, sodium lauryl sulfate, sodium phosphate monobasic, flavor, xanthan gum, tetrapotassium pyrophosphate, sodium benzoate, sodium saccharin, mica, sodium hydroxide, titanium dioxide, FD&C blue no. 1

Prevident 5000 Booster - Clinical Pharmacology

Frequent topical applications to the teeth with preparations having a relatively high fluoride content increase tooth resistance to acid dissolution and enhance penetration of the fluoride ion into tooth enamel.

Indications and Usage for Prevident 5000 Booster

A dental caries preventive; for once daily self-applied topical use. It is well established that 1.1% sodium fluoride is safe and extraordinarily effective as a caries preventive when applied frequently with mouthpiece applicators. 1-4 PreviDent® 5000 Booster brand of 1.1% sodium fluoride toothpaste in a squeeze bottle is easily applied onto a toothbrush. This prescription toothpaste should be used once daily in place of your regular toothpaste unless otherwise instructed by your dental professional. May be used in areas where drinking water is fluoridated since topical fluoride cannot produce fluorosis. (See WARNINGS for exception.)

Contraindications

Do not use in pediatric patients under age 6 years unless recommended by a dentist or physician.

Warnings

Prolonged daily ingestion may result in various degrees of dental fluorosis in pediatric patients under age 6 years, especially if the water fluoridation exceeds 0.6 ppm, since younger pediatric patients frequently cannot perform the brushing process without significant swallowing. Use in pediatric patients under age 6 years requires special supervision to prevent repeated swallowing of toothpaste which could cause dental fluorosis. Pediatric patients under age 12 should be supervised in the use of this product. Read directions carefully before using. Keep out of reach of infants and children.

Precautions

General

Not for systemic treatment. DO NOT SWALLOW.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a study conducted in rodents, no carcinogenesis was found in male and female mice and female rats treated with fluoride at dose levels ranging from 4.1 to 9.1 mg/kg of body weight. Equivocal evidence of carcinogenesis was reported in male rats treated with 2.5 and 4.1 mg/kg of body weight. In a second study, no carcinogenesis was observed in rats, males or females, treated with fluoride up to 11.3 mg/kg of body weight. Epidemiological data provide no credible evidence for an association between fluoride, either naturally occurring or added to drinking water, and risk of human cancer.

Fluoride ion is not mutagenic in standard bacterial systems. It has been shown that fluoride ion has potential to induce chromosome aberrations in cultured human and rodent cells at doses much higher than those to which humans are exposed. In vivo data are conflicting. Some studies report chromosome damage in rodents, while other studies using similar protocols report negative results.

Potential adverse reproductive effects of fluoride exposure in humans has not been adequately evaluated. Adverse effects on reproduction were reported for rats, mice, fox, and cattle exposed to 100 ppm or greater concentrations of fluoride in their diet or drinking water. Other studies conducted in rats demonstrated that lower concentrations of fluoride (5 mg/kg of body weight) did not result in impaired fertility and reproductive capabilities.

Pregnancy

Teratogenic Effects

Pregnancy Category B

It has been shown that fluoride crosses the placenta of rats, but only 0.01% of the amount administered is incorporated in fetal tissue. Animal studies (rats, mice, rabbits) have shown that fluoride is not a teratogen. Maternal exposure to 12.2 mg fluoride/kg of body weight (rats) or 13.1 mg/kg of body weight (rabbits) did not affect the litter size or fetal weight and did not increase the frequency of skeletal or visceral malformations. There are no adequate and well-controlled studies in pregnant women. However, epidemiological studies conducted in areas with high levels of naturally fluoridated water showed no increase in birth defects. Heavy exposure to fluoride during in utero development may result in skeletal fluorosis which becomes evident in childhood.

Nursing Mothers

It is not known if fluoride is excreted in human milk. However, many drugs are excreted in milk, and caution should be exercised when products containing fluoride are administered to a nursing woman. Reduced milk production was reported in farm-raised fox when the animals were fed a diet containing a high concentration of fluoride (98-137 mg/kg of body weight). No adverse effects on parturition, lactation, or offspring were seen in rats administered fluoride up to 5 mg/kg of body weight.

Pediatric Use

The use of PreviDent® 5000 Booster in pediatric age groups 6 to 16 years as a caries preventive is supported by pioneering clinical studies with 1.1% sodium fluoride gels in mouth trays in students age 11 to 14 years conducted by Englander et al. 2-4 Safety and effectiveness in pediatric patients below the age of 6 years have not been established. Please refer to the CONTRAINDICATIONS and WARNINGS sections.

Geriatric Use

Of the total number of subjects in clinical studies of 1.1% (w/v) sodium fluoride, 15 percent were 65 and over, while 1 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions.5

Adverse Reactions

Allergic reactions and other idiosyncrasies have been rarely reported.

Overdosage

Accidental ingestion of large amounts of fluoride may result in acute burning in the mouth and sore tongue. Nausea, vomiting, and diarrhea may occur soon after ingestion (within 30 minutes) and are accompanied by salivation, hematemesis, and epigastric cramping abdominal pain. These symptoms may persist for 24 hours. If less than 5 mg fluoride/kg body weight (i.e., less than 2.3 mg fluoride/lb body weight) have been ingested, give calcium (e.g., milk) orally to relieve gastrointestinal symptoms and observe for a few hours. If more than 5 mg fluoride/kg body weight (i.e., more than 2.3 mg fluoride/lb body weight) have been ingested, induce vomiting, give orally soluble calcium (e.g., milk, 5% calcium gluconate or calcium lactate solution) and immediately seek medical assistance. For accidental ingestion of more than 15 mg fluoride/kg of body weight (i.e., more than 6.9 mg fluoride/lb body weight), induce vomiting and admit immediately to a hospital facility.

A treatment dose (a thin ribbon) of PreviDent® 5000 Booster contains approximately 2.5 mg fluoride. A 3.4 FL OZ (100 mL) bottle contains approximately 608 mg fluoride.

Prevident 5000 Booster Dosage and Administration

Follow these instructions unless otherwise instructed by your dental professional:

1. Adults and pediatric patients 6 years of age or older, apply a thin ribbon of PreviDent® 5000 Booster to a toothbrush. Brush thoroughly once daily for two minutes, preferably at bedtime, in place of your regular toothpaste.


2. After use, adults expectorate. For best results, do not eat, drink, or rinse for 30 minutes. Pediatric patients, ages 6-16 years, expectorate after use and rinse mouth thoroughly.

How is Prevident 5000 Booster Supplied

3.4 FL OZ (100 mL) in plastic bottles. Spearmint: NDC 0126-0075-92, Fruitastic™: NDC 0126-0076-92

STORAGE

Store at Controlled Room Temperature, 68-77°F (20-25°C)

REFERENCES

1. American Dental Association, Accepted Dental Therapeutics Ed. 40 (Chicago, 1984): 405-407.


2. H.R. Englander et al., JADA 75 (1967): 638-644.


3. H.R. Englander et al., JADA 78 (1969): 783-787.


4. H.R. Englander et al., JADA 83 (1971): 354-358.


5. Data on file, Colgate Oral Pharmaceuticals.

Questions? Comments? Please Call 1-800-962-2345

www.colgateprofessional.com

Fruitastic is a licensed trademark of National Fruit Products Co. Inc.

PRINCIPAL DISPLAY PANEL 100 mL Bottle

NDC 0126-0075-92

Colgate®

PreviDent®

5000ppm

BOOSTER

1.1% Sodium Fluoride

PRESCRIPTION STRENGTH

TOOTHPASTE

SPEARMINT

3.4 FL OZ (100 mL)

Rx Only

P10001320

PREVIDENT  5000 BOOSTER sodium fluoride  gel, dentifrice

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0126-0075 Route of Administration DENTAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sodium fluoride (fluoride ion) Sodium fluoride 13.4 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color BLUE Score      Shape Size Flavor SPEARMINT Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0126-0075-92 100 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved drug other		07/06/2009

Labeler - Colgate-Palmolive Company (055002195)

Revised: 07/2009Colgate-Palmolive Company

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Ergoloid Mesylates

Pronunciation: ER-goe-loid MES-i-lates
Generic Name: Ergoloid Mesylates
Brand Name: Hydergine

Ergoloid Mesylates is used for:

Treating symptoms of declined mental capacity (memory, mood, and behavior problems) in certain patients older than 60 years of age. It may also be used for other conditions as determined by your doctor.

Ergoloid Mesylates is an ergot alkaloid. Exactly how it works is unknown.

Do NOT use Ergoloid Mesylates if:

• you are allergic to any ingredient in Ergoloid Mesylates


• you have certain mental problems (psychosis)


• you are taking HIV protease inhibitors (eg, delavirdine, indinavir, nelfinavir, ritonavir), efavirenz, a ketolide antibiotic (eg, telithromycin), a macrolide antibiotic (eg, clarithromycin, erythromycin), or selective 5-HT agonists (eg, sumatriptan, eletriptan)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Ergoloid Mesylates:

Some medical conditions may interact with Ergoloid Mesylates. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are planning to become pregnant or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with Ergoloid Mesylates. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Clotrimazole, ergot alkaloids (eg, ergotamine), fluconazole, fluoxetine, fluvoxamine, grapefruit juice, nefazodone, saquinavir, or zileuton because side effects of Ergoloid Mesylates may be increased


• HIV protease inhibitors (eg, delavirdine, indinavir, nelfinavir, ritonavir), efavirenz, ketolide antibiotics (eg, telithromycin), macrolide antibiotics (eg, erythromycin, clarithromycin), or selective 5-HT agonists (eg, sumatriptan, eletriptan) because the risk of severe side effects, including irregular heartbeat or decreased oxygen to the extremities (eg, hands, feet) or brain, may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Ergoloid Mesylates may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Ergoloid Mesylates:

Use Ergoloid Mesylates as directed by your doctor. Check the label on the medicine for exact dosing instructions. Check the label on the medicine for exact dosing instructions.

• Ergoloid Mesylates may be taken with or without food.


• Do not use Ergoloid Mesylates for more than 1 week unless instructed by your doctor.


• If you miss a dose of Ergoloid Mesylates, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. If you miss more than 1 dose, contact your doctor.

Ask your health care provider any questions you may have about how to use Ergoloid Mesylates.

Important safety information:

• Improvement is usually gradual. You may not see results for up to 3 to 4 weeks.


• Do not exceed the recommended dose or use Ergoloid Mesylates for longer than prescribed without checking with your doctor.


• Your doctor should evaluate you periodically while you are taking Ergoloid Mesylates to determine if you are still benefiting from it or whether you have a specific mental or mood problem that might benefit from a different medicine.


• Use Ergoloid Mesylates with extreme caution in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use Ergoloid Mesylates if you are pregnant. If you suspect that you could be pregnant, contact your doctor immediately. Ergoloid Mesylates is excreted in breast milk. Do not breast-feed while taking Ergoloid Mesylates.

Possible side effects of Ergoloid Mesylates:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Stomach upset; temporary nausea.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Ergoloid Mesylates side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Ergoloid Mesylates:

Store Ergoloid Mesylates at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Ergoloid Mesylates out of the reach of children and away from pets.

General information:

• If you have any questions about Ergoloid Mesylates, please talk with your doctor, pharmacist, or other health care provider.


• Ergoloid Mesylates is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Ergoloid Mesylates. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Veramyst

fluticasone furoate

Dosage Form: nasal spray
FULL PRESCRIBING INFORMATION

Indications and Usage for Veramyst

Treatment of Allergic Rhinitis

Veramyst® (fluticasone furoate) Nasal Spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older.

Veramyst Dosage and Administration

Administer Veramyst Nasal Spray by the intranasal route only. Prime Veramyst Nasal Spray before using for the first time by shaking the contents well and releasing 6 sprays into the air away from the face. When Veramyst Nasal Spray has not been used for more than 30 days or if the cap has been left off the bottle for 5 days or longer, prime the pump again until a fine mist appears. Shake Veramyst Nasal Spray well before each use.

Adults and Adolescents Aged 12 Years and Older

The recommended starting dosage is 110 mcg once daily administered as 2 sprays (27.5 mcg/spray) in each nostril. Titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage to 55 mcg (1 spray in each nostril) once daily may be effective in maintaining control of allergic rhinitis symptoms.

Children Aged 2 to 11 Years

The recommended starting dosage in children is 55 mcg once daily administered as 1 spray (27.5 mcg/spray) in each nostril. Children not adequately responding to 55 mcg may use 110 mcg (2 sprays in each nostril) once daily. Once symptoms have been controlled, the dosage may be decreased to 55 mcg once daily.

Dosage Forms and Strengths

Veramyst Nasal Spray is a nasal spray suspension. Each spray (50 microliters) delivers 27.5 mcg of fluticasone furoate.

Contraindications

Veramyst Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.3)].

Warnings and Precautions

Local Nasal Effects

Epistaxis and Nasal Ulceration: In clinical studies of 2 to 52 weeks’ duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with Veramyst Nasal Spray than those who received placebo [see Adverse Reactions (6.1)].

Candida Infection: Evidence of localized infections of the nose with Candida albicans was seen on nasal exams in 7 of 2,745 patients treated with Veramyst Nasal Spray during clinical trials and was reported as an adverse event in 3 patients. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of Veramyst Nasal Spray. Therefore, patients using Veramyst Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.

Nasal Septal Perforation: Postmarketing cases of nasal septal perforation have been reported in patients following the intranasal application of Veramyst Nasal Spray [see Adverse Reactions (6.2)].

Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Veramyst Nasal Spray until healing has occurred.

Glaucoma and Cataracts

Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month study in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week study in 558 children aged 2 to 11 years. The patients had perennial allergic rhinitis and were treated with either Veramyst Nasal Spray (110 mcg once daily in adult and adolescent patients and 55 or 110 mcg once daily in pediatric patients) or placebo. Intraocular pressure remained within the normal range (<21 mmHg) in ≥98% of the patients in any treatment group in both studies. However, in the 12-month study in adolescents and adults, 12 patients, all treated with Veramyst Nasal Spray 110 mcg once daily, had intraocular pressure measurements that increased above normal levels (≥21 mmHg). In the same study, 7 patients (6 treated with Veramyst Nasal Spray 110 mcg once daily and 1 patient treated with placebo) had cataracts identified during the study that were not present at baseline.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of Veramyst Nasal Spray. Discontinue Veramyst Nasal Spray if such reactions occur [see Contraindications (4)].

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or have not been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox or measles develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections.

Hypothalamic-Pituitary-Adrenal Axis Effects

Hypercorticism and Adrenal Suppression: When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Veramyst Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.

Use of Cytochrome P450 3A4 Inhibitors

Coadministration with ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. Use caution with the coadministration of Veramyst Nasal Spray and other potent cytochrome P450 3A4(CYP3A4) inhibitors, such as ketoconazole [see Drug Interactions (7)].

Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving Veramyst Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including Veramyst Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].

Adverse Reactions

Systemic and local corticosteroid use may result in the following:

• Epistaxis, ulcerations, Candida albicans infection, impaired wound healing, and nasal septal perforation [see Warnings and Precautions (5.1)]


• Cataracts and glaucoma [see Warnings and Precautions (5.2)]


• Immunosuppression [see Warnings and Precautions (5.4)]


• Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)]

Clinical Trials Experience

The safety data described below reflect exposure to Veramyst Nasal Spray in 1,563 patients with seasonal or perennial allergic rhinitis in 9 controlled clinical trials of 2 to 12 weeks’ duration. The data from adults and adolescents are based upon 6 clinical trials in which 768 patients with seasonal or perennial allergic rhinitis (473 females and 295 males aged 12 years and older) were treated with Veramyst Nasal Spray 110 mcg once daily for 2 to 6 weeks. The racial distribution of adult and adolescent patients receiving Veramyst Nasal Spray was 82% white, 5% black, and 13% other. The data from pediatric patients are based upon 3 clinical trials in which 795 children with seasonal or perennial rhinitis (352 females and 443 males aged 2 to 11 years) were treated with Veramyst Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks. The racial distribution of pediatric patients receiving Veramyst Nasal Spray was 75% white, 11% black, and 14% other.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults and Adolescents Aged 12 Years and Older: Overall adverse reactions were reported with approximately the same frequency by patients treated with Veramyst Nasal Spray and those receiving placebo. Less than 3% of patients in clinical trials discontinued treatment because of adverse reactions. The rate of withdrawal among patients receiving Veramyst Nasal Spray was similar or lower than the rate among patients receiving placebo.

Table 1 displays the common adverse reactions (>1% in any patient group receiving Veramyst Nasal Spray) that occurred more frequently in patients aged 12 years and older treated with Veramyst Nasal Spray compared with placebo-treated patients.

Table 1. Adverse Reactions With >1% Incidence in Controlled Clinical Trials of 2 to 6 Weeks’ Duration With Veramyst Nasal Spray in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

Adverse Event	Adult and Adolescent Patients Aged 12 Years and Older
	Vehicle Placebo (n = 774)	Veramyst Nasal Spray 110 mcg Once Daily (n = 768)
Headache	54 (7%)	72 (9%)
Epistaxis	32 (4%)	45 (6%)
Pharyngolaryngeal pain	8 (1%)	15 (2%)
Nasal ulceration	3 (<1%)	11 (1%)
Back pain	7 (<1%)	9 (1%)

There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger subjects.

Pediatric Patients Aged 2 to 11 Years: In the 3 clinical trials in pediatric patients aged 2 to <12 years, overall adverse reactions were reported with approximately the same frequency by patients treated with Veramyst Nasal Spray and those receiving placebo. Table 2 displays the common adverse reactions (>3% in any patient group receiving Veramyst Nasal Spray), that occurred more frequently in patients aged 2 to 11 years treated with Veramyst Nasal Spray compared with placebo-treated patients.

Table 2. Adverse Reactions With >3% Incidence in Controlled Clinical Trials of 2 to 12 Weeks’ Duration With Veramyst Nasal Spray in Pediatric Patients With Seasonal or Perennial Allergic Rhinitis

Adverse Event	Pediatric Patients Aged 2 to <12 Years
	Vehicle Placebo (n = 429)	Veramyst Nasal Spray 55 mcg Once Daily (n = 369)	Veramyst Nasal Spray 110 mcg Once Daily (n = 426)
Headache	31 (7%)	28 (8%)	33 (8%)
Nasopharyngitis	21 (5%)	20 (5%)	21 (5%)
Epistaxis	19 (4%)	17 (5%)	17 (4%)
Pyrexia	7 (2%)	17 (5%)	19 (4%)
Pharyngolaryngeal pain	14 (3%)	16 (4%)	12 (3%)
Cough	12 (3%)	12 (3%)	16 (4%)

There were no differences in the incidence of adverse reactions based on gender or race. Pyrexia occurred more frequently in children aged 2 to <6 years compared with children aged 6 to <12 years.

Long-Term (52-Week) Safety Trial: In a 52-week, placebo-controlled, long-term safety trial, 605 patients (307 females and 298 males aged 12 years and older) with perennial allergic rhinitis were treated with Veramyst Nasal Spray 110 mcg once daily for 12 months and 201 were treated with placebo nasal spray. While most adverse reactions were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received Veramyst Nasal Spray (123/605, 20%) than in patients who received placebo (17/201, 8%). Epistaxis tended to be more severe in patients treated with Veramyst Nasal Spray. All 17 reports of epistaxis that occurred in patients who received placebo were of mild intensity, while 83, 39, and 1 of the total 123 epistaxis events in patients treated with Veramyst Nasal Spray were of mild, moderate, and severe intensity, respectively. No patient experienced a nasal septal perforation during this trial.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of Veramyst Nasal Spray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone furoate or a combination of these factors.

Immune System Disorders: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.

Respiratory, Thoracic, and Mediastinal Disorders: Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness, and nasal septal perforation.

Drug Interactions

Fluticasone furoate is cleared by extensive first-pass metabolism mediated by CYP3A4. In a drug interaction study of intranasal fluticasone furoate and the CYP3A4 inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects receiving fluticasone furoate and ketoconazole had measurable but low levels of fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo. Based on this study and the low systemic exposure, there was a 5% reduction in 24-hour serum cortisol levels with ketoconazole compared with placebo. The data from this study should be carefully interpreted because the study was conducted with ketoconazole 200 mg once daily rather than 400 mg, which is the maximum recommended dosage. Therefore, caution is required with the coadministration of Veramyst Nasal Spray and ketoconazole or other potent CYP3A4 inhibitors.

Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, coadministration of Veramyst Nasal Spray with the potent CYP3A4 inhibitor ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. High exposure to corticosteroids increases the potential for systemic side effects, such as cortisol suppression.

Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to significantly alter the cytochrome P450-mediated metabolism of other compounds at clinically relevant intranasal dosages.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.

There were no teratogenic effects in rats and rabbits at inhaled fluticasone furoate dosages of up to 91 and 8 mcg/kg/day, respectively (approximately 7 and 1 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). There was also no effect on pre- or post-natal development in rats treated with up to 27 mcg/kg/day by inhalation during gestation and lactation (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Veramyst Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Nursing Mothers

It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Since there are no data from controlled trials on the use of intranasal fluticasone furoate by nursing mothers, caution should be exercised when Veramyst Nasal Spray is administered to a nursing woman.

Pediatric Use

Controlled clinical trials with Veramyst Nasal Spray included 1,224 patients aged 2 to 11 years and 344 adolescent patients aged 12 to 17 years [see Clinical Studies (14)]. The safety and effectiveness of Veramyst Nasal Spray in children younger than 2 years have not been established.

Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Veramyst Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including Veramyst Nasal Spray, each patient’s dose should be titrated to the lowest dosage that effectively controls his/her symptoms.

The potential for Veramyst Nasal Spray to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

Geriatric Use

Clinical studies of Veramyst Nasal Spray did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Use Veramyst Nasal Spray with caution in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Renal Impairment

No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Overdosage

Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.4)]. There are no data on the effects of acute or chronic overdosage with Veramyst Nasal Spray. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical studies (with dosages of up to 440 mcg/day for 2 weeks [4 times the maximum recommended daily dose]), overdose is unlikely to require any therapy other than observation.

Intranasal administration of up to 2,640 mcg/day (24 times the recommended adult dose) of fluticasone furoate was administered to healthy human volunteers for 3 days. Single- and repeat-dose studies with orally inhaled fluticasone furoate doses of 50 to 4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher. The oral median lethal dose in mice and rats was >2,000 mg/kg (approximately 74,000 and 147,000 times, respectively, the maximum recommended daily intranasal dose in adults and 52,000 and 105,000 times, respectively, the maximum recommended daily intranasal dose in children, on a mcg/m2 basis).

Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of Veramyst Nasal Spray contains approximately 3 mg of fluticasone furoate, and the bioavailability of fluticasone furoate is <1% for 2.64 mg/day given intranasally and 1% for 2 mg/day given as an oral solution.

Veramyst Description

Fluticasone furoate, the active component of Veramyst Nasal Spray, is a synthetic fluorinated corticosteroid having the chemical name (6α,11β,16α,17α) - 6,9 - difluoro - 17 - {[(fluoro - methyl)thio]carbonyl} - 11 - hydroxy - 16 - methyl - 3 - oxoandrosta - 1,4 - dien - 17 - yl 2-furancarboxylate and the following chemical structure:

Fluticasone furoate is a white powder with a molecular weight of 538.6, and the empirical formula is C27H29F3O6S. It is practically insoluble in water.

Veramyst Nasal Spray is an aqueous suspension of micronized fluticasone furoate for topical administration to the nasal mucosa by means of a metering (50 microliters), atomizing spray pump. After initial priming [see Dosage and Administration (2)], each actuation delivers 27.5 mcg of fluticasone furoate in a volume of 50 microliters of nasal spray suspension. Veramyst Nasal Spray also contains 0.015% w/w benzalkonium chloride, dextrose anhydrous, edetate disodium, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, and purified water. It has a pH of approximately 6.

Veramyst - Clinical Pharmacology

Mechanism of Action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats.

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

Pharmacodynamics

Adrenal Function: The effects of Veramyst Nasal Spray on adrenal function have been evaluated in 4 controlled clinical trials in patients with perennial allergic rhinitis. Two 6-week clinical trials were designed specifically to assess the effect of Veramyst Nasal Spray on the HPA axis with assessments of both 24-hour urinary cortisol excretion and serum cortisol levels in domiciled patients. In addition, one 52-week safety study and one 12-week safety and efficacy study included assessments of 24-hour urinary cortisol excretion. Details of the studies and results are described below. In all 4 studies, since serum fluticasone determinations were generally below the limit of quantification, compliance was assured by efficacy assessments.

Clinical Trials Specifically Designed to Assess Hypothalamic-Pituitary-Adrenal Axis Effect: In a 6-week randomized, double-blind, parallel-group study in adult and adolescent patients aged 12 years and older with perennial allergic rhinitis, Veramyst Nasal Spray 110 mcg was compared with both placebo nasal spray and prednisone as a positive-control group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period. Adrenal function was assessed by 24-hour urinary cortisol excretion before and after 6 weeks of treatment and by serial serum cortisol levels. Patients were domiciled for collection of 24-hour urinary cortisol. After 6 weeks of treatment, there was a change from baseline in the mean 24-hour urinary cortisol excretion in the group treated with Veramyst Nasal Spray (n = 43) of -1.16 mcg/day compared with -3.48 mcg/day in the placebo group (n = 42). The difference from placebo in the group treated with Veramyst Nasal Spray was 2.32 mcg/day (95% CI: -6.76, 11.39). Urinary cortisol data were not available for the positive-control (prednisone) treatment group. For serum cortisol levels, after 6 weeks of treatment there was a change from baseline in the mean (0-24 hours) of -0.38 and 0.08 mcg/dL for the group treated with Veramyst Nasal Spray (n = 43) and the placebo group (n = 44), respectively, with a difference between the group treated with Veramyst Nasal Spray and the placebo group of -0.47 mcg/dL (95% CI: -1.31, 0.37). For comparison, in the positive-control (prednisone, n = 12) treatment group, there was a change in mean serum cortisol (0-24 hours) from baseline of -4.49 mcg/dL with a difference between the prednisone and placebo group of -4.57 mcg/dL (95% CI: -5.83, -3.31).

The second 6-week study conducted in children aged 2 to 11 years was of similar design to the adult study, including adrenal function assessments, but did not include a prednisone positive-control arm. Patients were treated once daily with Veramyst Nasal Spray 110 mcg or placebo nasal spray. After 6 weeks of treatment, there was a change in the mean 24-hour urinary cortisol excretion in the group treated with Veramyst Nasal Spray (n = 43) of 0.49 mcg/day compared with 1.92 mcg/day in the placebo group (n = 41), with a difference between the group treated with Veramyst Nasal Spray and the placebo group of -1.43 mcg/day (95% CI: -5.21, 2.35). For serum cortisol levels, after 6 weeks, there was a change from baseline in mean (0-24 hours) of -0.34 and -0.23 mcg/dL for the group treated with Veramyst Nasal Spray (n = 48) and for the placebo group (n = 47), respectively, with a difference between the group treated with Veramyst Nasal Spray and the placebo group of -0.11 mcg/dL (95% CI: -0.88, 0.66).

Additional Hypothalamic-Pituitary-Adrenal Axis Assessments: In the 52-week safety trial in adolescents and adults aged 12 years and older with perennial allergic rhinitis, Veramyst Nasal Spray 110 mcg (n = 605) was compared with placebo nasal spray (n = 201). Adrenal function was assessed by 24-hour urinary cortisol excretion in a subset of patients who received Veramyst Nasal Spray (n = 370) or placebo (n = 120) before and after 52 weeks of treatment. After 52 weeks of treatment, the mean change from baseline 24-hour urinary cortisol excretion was 5.84 mcg/day in the group treated with Veramyst Nasal Spray and 3.34 mcg/day in the placebo group. The difference from placebo in mean change from baseline 24-hour urinary cortisol excretion was 2.50 mcg/day (95% CI: -5.49, 10.49).

In the 12-week safety and efficacy trial in children aged 2 to 11 years with perennial allergic rhinitis, Veramyst Nasal Spray 55 mcg (n = 185) and Veramyst Nasal Spray 110 mcg (n = 185) were compared with placebo nasal spray (n = 188). Adrenal function was assessed by measurement of 24-hour urinary free cortisol in a subset of patients who were aged 6 to 11 years (103 to 109 patients per group) before and after 12 weeks of treatment. After 12 weeks of treatment, there was a decrease in mean 24-hour urinary cortisol excretion from baseline in the group treated with Veramyst Nasal Spray 55 mcg (n = 109) of -2.93 mcg/day and in the group treated with Veramyst Nasal Spray 110 mcg (n = 103) of -2.07 mcg/day compared with an increase in the placebo group (n = 107) of 0.08 mcg/day. The difference from placebo in mean change from baseline in 24-hour urinary cortisol excretion for the group treated with Veramyst Nasal Spray 55 mcg was -3.01 mcg/day (95% CI: -6.16, 0.13) and -2.14 mcg/day (95% CI: -5.33, 1.04) for the group treated with Veramyst Nasal Spray 110 mcg.

When the results of the HPA axis assessments described above are taken as a whole, an effect of intranasal fluticasone furoate on adrenal function cannot be ruled out, especially in pediatric patients.

Cardiac Effects: A QT/QTc study did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo and positive (a single dose of 400 mg oral moxifloxacin) controlled cross-over study. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). While a single dose of fluticasone furoate had no effect on the QTc interval, the effects of fluticasone furoate may not be at steady state following single dose. The effect of fluticasone furoate on the QTc interval following multiple dose administration is unknown.

Pharmacokinetics

Absorption: Following intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. At the highest recommended intranasal dosage of 110 mcg once daily for up to 12 months in adults and up to 12 weeks in children, plasma concentrations of fluticasone furoate are typically not quantifiable despite the use of a sensitive HPLC-MS/MS assay with a lower limit of quantification (LOQ) of 10 pg/mL. However, in a few isolated cases (<0.3%) fluticasone furoate was detected in high concentrations above 500 pg/mL, and in a single case the concentration was as high as 1,430 pg/mL in the 52-week study. There was no relationship between these concentrations and cortisol levels in these subjects. The reasons for these high concentrations are unknown.

Absolute bioavailability was evaluated in 16 male and female subjects following supratherapeutic dosages of fluticasone furoate (880 mcg given intranasally at 8-hour intervals for 10 doses, or 2,640 mcg/day). The average absolute bioavailability was 0.50% (90% CI: 0.34%, 0.74%).

Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral solution and intravenous dosing of radiolabeled drug have demonstrated that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. Oral bioavailability is on average 1.26%, and the majority of the circulating radioactivity is due to inactive metabolites.

Distribution: Following intravenous administration, the mean volume of distribution at steady state is 608 L.

Binding of fluticasone furoate to human plasma proteins is greater than 99%.

Metabolism: In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone. Fluticasone furoate is cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism via CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17β-carboxylic acid metabolite.

Elimination: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. The elimination phase half-life averaged 15.1 hours following intravenous administration.

Population Pharmacokinetics: Fluticasone furoate is typically not quantifiable in plasma following intranasal dosing of 110 mcg once daily with the exception of isolated cases of very high plasma levels (see Absorption). Overall, quantifiable levels (>10 pg/mL) were observed in <31% of patients aged 12 years and older and in <16% of children (aged 2 to 11 years) following intranasal dosing of 110 mcg once daily and in <7% of children following intranasal dosing of 55 mcg once daily. There was no evidence to suggest that the presence or absence of detectable levels of fluticasone furoate was related to gender, age, or race.

Hepatic Impairment: Reduced liver function may affect the elimination of corticosteroids. Since fluticasone furoate undergoes extensive first-pass metabolism by the hepatic CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. A study of a single 400-mcg dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh Class B) resulted in increased Cmax (42%) and AUC(0-∞) (172%), resulting in an approximately 20% reduction in serum cortisol level in patients with hepatic impairment compared with healthy subjects. The systemic exposure would be expected to be higher than that observed had the study been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use Veramyst Nasal Spray with caution in patients with severe hepatic impairment.

Renal Impairment: Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of dose-related material is excreted in urine. No dosage adjustment is required in patients with renal impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at doses of up to 9 and 19 mcg/kg/day, respectively (less than the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis).

Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled fluticasone furoate doses of up to 24 and 91 mcg/kg/day, respectively (approximately 2 and 7 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).

Clinical Studies

Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older: The efficacy and safety of Veramyst Nasal Spray was evaluated in 5 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 4 weeks’ duration in adult and adolescent patients aged 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 5 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, three 2-week confirmatory efficacy trials in patients with seasonal allergic rhinitis, and one 4-week efficacy trial in patients with perennial allergic rhinitis. These trials included 1,829 patients (697 males and 1,132 females). About 75% of patients were Caucasian, and the mean age was 36 years. Of these patients, 722 received Veramyst Nasal Spray 110 mcg once daily administered as 2 sprays in each nostril.

Assessment of efficacy was based on total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients’ scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective(rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required patients to record symptom severity at the time immediately prior to the next dose. Morning and evening rTNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS (AM iTNSS) reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval.

Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). TOSS is calculated as the sum of the patients’ scoring of the 3 individual ocular symptoms (itching/burning, tearing/watering, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous scores (iTOSS). To assess efficacy, rTOSS and AM iTOSS were evaluated as described above for the TNSS. Patients’ perceptions of disease-specific quality of life were evaluated through use of the RQLQ, which assesses the impact of allergic rhinitis treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = no impairment and 6 = maximum impairment. An overall RQLQ score is calculated from the mean of all items in the instrument. An absolute difference of ≥0.5 in mean change from baseline over placebo is considered the minimally important difference (MID) for the RQLQ.

Dose-Ranging Trial: The dose-ranging trial was a 2-week trial that evaluated the efficacy of 4 dosages of fluticasone furoate nasal spray (440, 220, 110, and 55 mcg) in patients with seasonal allergic rhinitis. In this trial, each of the 4 dosages of fluticasone furoate nasal spray demonstrated greater decreases in the rTNSS than placebo, and the difference was statistically significant (Table 3).

Table 3. Mean Change From Baseline in Reflective Total Nasal Symptom Score Over 2 Weeks in Patients With Seasonal Allergic Rhinitis

Treatment	n	Baseline (AM + PM)	Change From Baseline	Difference From Placebo
				LS Mean	95% CI	P Value
Fluticasone furoate 440 mcg	130	9.6	-4.02	-2.19	-2.75, -1.62	<0.001
Fluticasone furoate 220 mcg	129	9.5	-3.19	-1.36	-1.93, -0.79