Viridal Duo 10 micrograms / ml,Powder and Solvent for Solution for Injection

1. Name Of The Medicinal Product

Viridal Duo 10 micrograms/ml, Powder and Solvent for Solution for Injection.

2. Qualitative And Quantitative Composition

Alprostadil 10 micrograms (used as a 1:1 clathrate complex with alfadex).

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Double chamber glass cartridge containing lyophilised powder and solvent for reconstitution (0.9% w/v sodium chloride solution).

The powder is white and odourless, and the isotonic sodium chloride solution is clear. The powder dissolves immediately to yield a clear solution.

4. Clinical Particulars

4.1 Therapeutic Indications

As an adjunct to the diagnostic evaluation of erectile dysfunction in adult males.

Treatment of erectile dysfunction in adult males.

4.2 Posology And Method Of Administration

The drug solution should be prepared shortly before the injection.

Prior to injection the needle should be screwed onto the tip of the injector. After disinfecting the tip of the cartridge with one of the alcohol swabs, the cartridge should then be inserted into the injector. By screwing the thread part clockwise, the cartridge is fixed in the injector. Then, the dry substance, which is inside the front chamber of the cartridge, is reconstituted with 1 ml sterile sodium chloride solution 0.9% in the bottom chamber. While holding the device in a vertical position with the needle upwards, the thread part should be screwed slowly until it will not go any further. The solvent will by-pass the upper stopper into the front chamber and dissolve the dry substance within a few seconds. As soon as the dry substance is reconstituted, the larger external and the smaller inner protective cap have to be removed from the needle. The air should then be expelled out of the cartridge and the prescribed dose adjusted precisely.

Unused solution must be discarded immediately.

Viridal Duo is injected into either the right or the left cavernous body of the penile shaft. Once the needle is in the cavernous body, the injection should be done within 5 to 10 seconds and is very easy without much resistance if the needle is in the correct position.

The development of an erection will start approximately 5 – 15 minutes after the injection.

Dosage for injection in the clinic

Injections for diagnostic evaluation and dose titration must be performed by the attending physician. He will determine an individual dose suitable to produce an erectile response for diagnostic purposes.

The recommended starting dose is 2.5 mcg Viridal Duo in patients with primary psychogenic or neurogenic origin of erectile dysfunction. In all other patients with erectile dysfunction 5 mcg Viridal Duo should be used as a starting dose. Dose adjustments may be performed in increments of about 2.5 mcg to 5 mcg Viridal Duo. Most of the patients require between 10 and 20 mcg per injection. Some patients may need to be titrated to higher doses. Doses exceeding 20 mcg should be prescribed with particular care in patients with cardiovascular risk factors. The dose per injection should never exceed 40 mcg.

Dosage for self-injection therapy at home

Before starting treatment at home, each patient or the patient's partner has to be taught by a physician how to prepare the drug and perform the injection. In no cases should the injection therapy be started without precise instructions by the physician. The patient should only use his optimum individual dosage, which has been pre-determined by his physician using the above-mentioned procedure. This dose should allow the patient to have an erection at home, which should not last longer than one hour. If he experiences prolonged erections beyond 2 hours but less than 4 hours, the patient is recommended to contact his physician to re-establish the dose of the drug. Maximum injection frequency recommended is 2 or 3 times a week with an interval of at least 24 hours between the injections.

Follow-up

After the first injections and at regular intervals, e.g. every three months, the physician should re-evaluate the patient. Any local adverse reaction, e.g. haematoma, fibrosis or nodules should be noted and controlled. Following discussion with the patient, an adjustment of dosage may be necessary.

4.3 Contraindications

Hypersensitivity to the active substances or to any other ingredients.

Patients with diseases causing priapism e.g. sickle-cell disease, leukaemia and multiple myeloma or patients with anatomical deformation of the penis as cavernosal fibrosis or Peyronie's disease. Patients with penis implants should not use Viridal Duo.

Viridal Duo should not be used in men for whom sexual activity is contraindicated.

4.4 Special Warnings And Precautions For Use

The physician should carefully select patients suitable for self-injection therapy.

Sexual stimulation and intercourse can lead to cardiac and/or pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease. Viridal Duo should be used with care in these patient groups and patients should be examined and cleared for stress resistance by a cardiologist before treatment.

Viridal Duo should be used with care in patients who have experienced transient ischaemic attacks.

Patients who experience a prolonged erection lasting longer than four hours should contact their physician immediately. Therefore it is recommended that the patient has an emergency telephone number of his attending physician or of a clinic experienced in therapy of erectile dysfunction. Prolonged erection may damage penile erectile tissue and lead to irreversible erectile dysfunction.

A benefit-risk evaluation is neccesary before using Viridal Duo in patients with pre-existing scarring, e.g. nodules of the cavernous body or pre-existing penile deviation or Peyronie's disease or clinically relevant phimosis, e.g. phimosis with risk of paraphimosis these patients should be treated with particular care, e.g. more frequent re-evaluation of the patient's condition.

Patients who have to be treated with alpha-adrenergic drugs due to prolonged erections (see: overdose) may in the case of concomitant therapy with monoamino-oxidase-inhibitors, develop a hypertensive crisis.

Other intracavernous drugs e.g. smooth muscle relaxing agents or alpha-adrenergic blocking agents may lead to prolonged erection and must not be used concomitantly. The effects of a combination therapy of alprostadil with oral, intraurethral or topical medicinal products for erectile dysfunction are currently unknown.

Patients with blood clotting disorders or patients on therapy influencing blood clotting parameters should be carefully selected for treatment by the treating physician and treated with special care, e.g. monitoring of the clotting parameters, patients should be thoroughly educated by the prescriber about the associated risks and advised to exercise sufficient manual pressure on the injection site. This is because of the increased risk of bleeding.

To prevent abuse, self-injection therapy with Viridal Duo should not be used by patients with drug addiction and/or disturbances of psychological or intellectual development.

In cases of excessive use, e.g. higher frequencies than recommended, an increased risk of penile scarring cannot be excluded.

Use of intracavernous alprostadil offers no protection from the transmission of sexually transmitted diseases. Individuals who use alprostadil should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). In some patients, injection of Viridal Duo can induce a small amount of bleeding at the injection site. In patients infected with blood borne diseases, this could increase the transmission of such diseases to the partner. For this reason we recommend that a condom is used for intercourse after injecting Viridal Duo.

Viridal Duo is for intracavernous injection. Subcutaneous injection or injections at areas of the penis other than the cavernous body should be avoided.

The injection should be performed under hygienic conditions to avoid infections. In any condition that precludes safe self-injection like poor manual dexterity, poor visual acuity or morbid obesity, the partner should be trained in the injection technique and should perform the injection.

Up to now, there is no clinical experience in patients under 18 and over 75 years of age.

Viridal Duo does not interfere with ejaculation and fertility.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of smooth muscle relaxing drugs like papaverine or other drugs inducing erection like alpha-adrenergic blocking agents may lead to prolonged erection and should not be used in parallel with Viridal Duo.

Risks exist when using alpha-adrenergic drugs to terminate prolonged erections in patients with cardiovascular disorders or receiving MAO inhibitors.

The effects of blood pressure lowering and vasodilating drugs may be increased.

4.6 Pregnancy And Lactation

The natural amount of PGE1 present in the sperm may be increased by the PGE1 present in Viridal Duo. In case the partner is pregnant, a condom should be used in order to avoid irritation of the vagina and a risk for the foetus.

4.7 Effects On Ability To Drive And Use Machines

Viridal Duo may rarely induce a transient drop of blood pressure with subsequent impairment of reactivity that could interfere with patient's ability to drive or operate machinery.

4.8 Undesirable Effects

Undesirable effects frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000).

During administration of Viridal Duo the following undesirable effects may be observed:

General disorders and administration site condition

Common: burning sensation during injection and after the injection, sensation of tension in the penis and pain of mostly mild intensity at the site of injection.

Uncommon: spotlike haemorrhage/ spotlike bruises at the site of puncture, haemosiderin deposits, reddening and swellings at the site of injection, swellings of the preputium or the glans, and headache.

Reproductive system and breast disorders

Common: fibrotic alterations (e.g. fibrotic nodules, plaques at the site of injection or in the corpus cavernosum) can occur during long-term treatment.

Uncommon: fibrotic alterations associated with slight penile axis deviations. Prolonged erections of more than 4 hours' duration are uncommon (mainly seen during dose titration).

Rare: fibrotic changes of the cavernous body during a long term treatment lasting up to 4 years.

Cardiac disorders

Rare: circulatory effects such as short periods of hypotension and/or vertigo or dizziness.

Immune system disorders

Rare: allergic reactions ranging from cutaneous hypersensitivity such as rash, erythema, urticaria to anaphylactic/anaphylactoid reactions.

4.9 Overdose

Symptoms

Full rigid erections lasting more than four hours.

If the patient experiences a prolonged erection, he is advised to contact his attending physician or a urologic clinic nearby immediately.

Treatment strategy

Treatment of prolonged erection should be done by a physician experienced in the field of erectile dysfunction. If prolonged erection occurs, the following is recommended:

If the erection has lasted less than six hours:

− observation of the erection because spontaneous flaccidity frequently occurs.

If the erection has lasted longer than six hours:

− cavernous body injection of alpha-adrenergic substances (e.g. phenylephrine or epinephrine (adrenaline)). Risks exist when using drugs in patients with cardiovascular disorders or receiving MAO inhibitors. All patients should be monitored for cardiovascular effects when these drugs are used to terminate prolonged erections.

or

− aspiration of blood from the cavernous body.

Accidental systemic injection of high doses

Single dose rising tolerance studies in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Starting with a 40 mcg bolus intravenous dose, the frequency of drug-related adverse events increased in a dose-dependent manner, characterised mainly by facial flushing.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: Other urologicals G04BX 05

Alprostadil [Prostaglandin E₁ (PGE₁)], the active ingredient of Viridal Duo, is an endogenous compound derived from the essential fatty acid dihomogammalinolenic acid. Alprostadil is a potent smooth muscle relaxant that produces vasodilation and occurs in high concentrations in the human seminal fluid. Pre-contracted isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery were relaxed by alprostadil, while other prostanoids were less effective. Alprostadil has been shown to bind to specific receptors in the cavernous tissue of human and non-human primates.

The binding of alprostadil to its receptors is accompanied by an increase in intracellular cAMP levels. Human cavernosal smooth muscle cells respond to alprostadil by releasing intracellular calcium. Since relaxation of smooth muscle is associated with a reduction of the cytoplasmic free calcium concentration, this effect may contribute to the relaxing activity of this prostanoid.

Intracavernous injection of alprostadil in healthy monkeys resulted in penile elongation and tumescence without rigidity. The cavernous arterial blood flow was increased for a mean duration of 20 min. In contrast, intracavernous application of alprostadil to rabbits and dogs caused no erectile response.

Systemic intravascular administration of alprostadil leads to a vasodilation and reduction of systemic peripheral vascular resistance. A decrease in blood pressure can be observed after administration of high doses. Alprostadil has also been shown in animal and in vitro tests to reduce platelet reactivity and neutrophil activation. Additional alprostadil activity has been reported: increase in fibrinolytic activity of fibroblasts, improvement of erythrocyte deformability and inhibition of erythrocyte aggregation; inhibition of the proliferative and mitotic activity of non-striated myocytes; inhibition of cholesterol synthesis and LDL-receptor activity; and an increase in the supply of oxygen and glucose to ischaemic tissue along with improved tissue utilisation of these substrates.

5.2 Pharmacokinetic Properties

After reconstitution, alprostadil (PGE₁) dissociates from the α-cyclodextrin clathrate, and the two components have independent fates.

In symptomatic volunteers, systemic mean endogenous PGE₁ venous plasma concentrations measured before intracavernous injection are approximately 1pg/ml. After injection of 20 mcg of alprostadil, the PGE₁ venous plasma concentrations increase rapidly to concentrations of about 10-20 pg/ml. The PGE₁ plasma concentrations return to concentrations close to the baseline within a few minutes. Approximately 90% of PGE₁ found in plasma is protein-bound.

Metabolism

Enzymatic oxidation of the C15-hydroxy group and reduction of the C13,14 double bond produce the primary metabolites, 15-keto-PGE₁, PGE_o (13,14-dihydro-PGE₁) and 15-keto-PGE_o. Only PGE_o and 15-keto-PGE_o have been detected in human plasma. Unlike the 15-keto metabolites, which are less pharmacologically active than the parent compound, PGE_o has a potency similar to that of PGE₁ in most respects.

In symptomatic volunteers, the mean endogenous PGE_o venous plasma concentrations measured before an intracavernous injection are approximately 1 pg/ml. After the injection of 20 mcg of alprostadil, the PGE_o plasma concentrations increase to concentrations of about 5 pg/ml.

Excretion

After further degradation of the primary metabolites by beta and omega oxidation, the resulting, more polar metabolites are excreted primarily with the urine (88%) and the faeces (12% ) and there is no evidence of tissue retention of PGE₁ or its metabolites.

5.3 Preclinical Safety Data

Studies on local tolerance following single and repeated intracavernous injections of alprostadil or alprostadil alfadex in rabbits and/or monkeys, in monkeys up to 6 months with daily injection revealed in general good local tolerance. Possible adverse effects like haematomas and inflammations are more likely related to the injection procedure.

Within the 6 months study in male monkeys, there were no adverse effects of alprostadil alfadex on male reproductive organs.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance in male and female rats treated with 40-200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose on a body weight basis (MHRD < 1 mcg/kg).

Alprostadil was not fetotoxic or teratogenic at doses up to 5000 mcg/kg/day (7500 times the MHRD) in rats, 200 mcg/kg/day (300 times the MHRD) in rabbits and doses up to 20 mcg/kg/day (30 times the MHRD) in guinea pigs or monkeys.

Mutagenicity studies with alprostadil alfadex revealed no risk of mutagenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder for injection:

Lactose monohydrates

Alfadex

Diluent:

Sodium chloride

Water for injection.

6.2 Incompatibilities

It is not intended that this medicinal product be mixed with other medicinal products, therefore, in the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Shelf life for the product as packaged for sale: 4 years.

Shelf life after reconstitution: for immediate use only.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Administration devices

1 reusable injector (starter kit)

1 double chamber cartridge with dry substance and 1 ml 0.9% sterile sodium chloride solution

1 injection needle 29G x ½ (0.33 mm x 12.7 mm)

1 alcohol swab to be obtained for each injection

1. Cartons containing one colourless glass double-chamber cartridge, one injection needle 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

2. Cartons containing two colourless glass double-chamber cartridges, two injection needles 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

3. Cartons containing one, two or six colourless glass double-chamber cartridges and corresponding number of injection needles 29 G x ½ (0.33 mm x 12.7 mm) without reusable injector.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Fix the injection needle onto the front part of the injector.

Disinfect the tip of the cartridge with one of the alcohol swabs. Insert the cartridge into the re-usable injector and fix it by screwing the thread part. Dissolve the drug substance in the front chamber of the cartridge by completely screwing the thread-part into the injector thus moving both rubber stoppers to the top of the cartridge and allowing the solvent in to the bottom chamber to reach the dry substance via the bypass of the cartridge. Shake slightly until a clear solution is produced.

Expel the air and adjust the prescribed dosage precisely prior to intracavernous injection.

After preparation of the solution, the injection must be performed using aseptic procedures into either the left or right cavernous body of the penile shaft. Care should be taken not to inject into penile vessels or nerves on the upper side of the penis and into the urethra on the under side. The injection should be completed within 5 to 10 seconds and manual pressure should be applied to the injection site for 2 to 3 minutes.

Unused solution must be discarded immediately.

Advice

The content of the front chamber of the cartridge consists of a white, dry powder, which forms a compact layer, approximately 8 mm in height. The layer may show cracks and crumble slightly.

In case of damage to the cartridge, the usually dry content of the front chamber becomes moist and sticky and extensively loses volume. Viridal Duo must not be used in this case.

The bottom chamber contains the clear, colourless sodium chloride solvent solution.

The dry substance dissolves immediately after addition of the sodium chloride solution. Initially after reconstitution the solution may appear slightly opaque due to the presence of bubbles. This is of no relevance and disappears within a short time to give a clear solution.

Disposal of needle: disable needle then dispose of in a sharps container.

Disposal of cartridge: no special requirements.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/0751

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd September 2010

10. Date Of Revision Of The Text

Cayston

aztreonam

Dosage Form: inhalation solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Cayston

Cayston® is indicated to improve respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa. Safety and effectiveness have not been established in pediatric patients below the age of 7 years, patients with FEV1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)].

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cayston and other antibacterial drugs, Cayston should be used only to treat patients with CF known to have Pseudomonas aeruginosa in the lungs.

Cayston Dosage and Administration

Dosing Information

The recommended dose of Cayston for both adults and pediatric patients 7 years of age and older is one single-use vial (75 mg of aztreonam) reconstituted with 1 mL of sterile diluent administered 3 times a day for a 28-day course (followed by 28 days off Cayston therapy). Dosage is not based on weight or adjusted for age. Doses should be taken at least 4 hours apart.

Cayston is administered by inhalation using an Altera® Nebulizer System. Patients should use a bronchodilator before administration of Cayston.

Instructions for Cayston Reconstitution

Cayston should be administered immediately after reconstitution. Do not reconstitute Cayston until ready to administer a dose.

Take one amber glass vial containing Cayston and one diluent ampule from the carton. To open the glass vial, carefully remove the metal ring by pulling the tab and remove the gray rubber stopper. Twist the tip off the diluent ampule and squeeze the liquid into the glass vial. Replace the rubber stopper, then gently swirl the vial until contents have completely dissolved.

The empty vial, stopper, and diluent ampule should be disposed of properly upon completion of dosing.

Instructions for Cayston Administration

Cayston is administered by inhalation using an Altera Nebulizer System. Cayston should not be administered with any other nebulizer. Cayston should not be mixed with any other drugs in the Altera Nebulizer Handset.

Cayston is not for intravenous or intramuscular administration.

Patients should use a bronchodilator before administration of Cayston. Short-acting bronchodilators can be taken between 15 minutes and 4 hours prior to each dose of Cayston. Alternatively, long-acting bronchodilators can be taken between 30 minutes and 12 hours prior to administration of Cayston. For patients taking multiple inhaled therapies, the recommended order of administration is as follows: bronchodilator, mucolytics, and lastly, Cayston.

To administer Cayston, pour the reconstituted solution into the handset of the nebulizer system. Turn the unit on. Place the mouthpiece of the handset in your mouth and breathe normally only through your mouth. Administration typically takes between 2 and 3 minutes. Further patient instructions on how to administer Cayston are provided in the FDA-approved patient labeling. Instructions on testing nebulizer functionality and cleaning the handset are provided in the Instructions for Use included with the nebulizer system.

Dosage Forms and Strengths

A dose of Cayston consists of a single-use vial of sterile, lyophilized aztreonam (75 mg) reconstituted with a 1 mL ampule of sterile diluent (0.17% sodium chloride). Reconstituted Cayston is administered by inhalation.

Contraindications

Cayston is contraindicated in patients with a known allergy to aztreonam.

Warnings and Precautions

Allergic Reactions

Severe allergic reactions have been reported following administration of aztreonam for injection to patients with no known history of exposure to aztreonam. In addition, allergic reaction with facial rash, facial swelling, and throat tightness was reported with Cayston in clinical trials. If an allergic reaction to Cayston occurs, stop administration of Cayston and initiate treatment as appropriate.

Caution is advised when administering Cayston to patients if they have a history of beta-lactam allergy, although patients with a known beta-lactam allergy have received Cayston in clinical trials and no severe allergic reactions were reported. A history of allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems, may be a risk factor, since cross-reactivity may occur.

Bronchospasm

Bronchospasm is a complication associated with nebulized therapies, including Cayston. Reduction of 15% or more in forced expiratory volume in 1 second (FEV1) immediately following administration of study medication after pretreatment with a bronchodilator was observed in 3% of patients treated with Cayston.

Decreases in FEV1 After 28-Day Treatment Cycle

In clinical trials, patients with increases in FEV1 during a 28-day course of Cayston were sometimes treated for pulmonary exacerbations when FEV1 declined after the treatment period. Healthcare providers should consider a patient's baseline FEV1 measured prior to Cayston therapy and the presence of other symptoms when evaluating whether post-treatment changes in FEV1 are caused by a pulmonary exacerbation.

Development of Drug-Resistant Bacteria

Prescribing Cayston in the absence of known Pseudomonas aeruginosa infection in patients with CF is unlikely to provide benefit and increases the risk of development of drug-resistant bacteria.

Adverse Reactions

Clinical Trials Experience

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

The safety of Cayston was evaluated in 344 patients from two placebo-controlled trials and one open-label follow-on trial. In controlled trials, 146 patients with CF received 75 mg Cayston 3 times a day for 28 days.

Table 1 displays adverse reactions reported in more than 5% of patients treated with Cayston 3 times a day in placebo-controlled trials. The listed adverse reactions occurred more frequently in Cayston-treated patients than in placebo-treated patients.

Table 1. Adverse Reactions Reported in more than 5% of Patients Treated with Cayston in the Placebo-Controlled Trials

Event (Preferred Term)	Placebo (N = 160) n (%)	Cayston 75 mg 3 times a day (N = 146) n (%)
Cough	82 (51%)	79 (54%)
Nasal congestion	19 (12%)	23 (16%)
Wheezing	16 (10%)	23 (16%)
Pharyngolaryngeal pain	17 (11%)	18 (12%)
Pyrexia	9 (6%)	19 (13%)
Chest discomfort	10 (6%)	11 (8%)
Abdominal Pain	8 (5%)	10 (7%)
Vomiting	7 (4%)	9 (6%)

Adverse reactions that occurred in less than 5% of patients treated with Cayston were bronchospasm (3%) [see Warnings and Precautions (5.2)] and rash (2%).

Drug Interactions

No formal clinical studies of drug interactions with Cayston have been conducted.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

No reproductive toxicology studies have been conducted with Cayston. However, studies were conducted with aztreonam for injection. Aztreonam has been shown to cross the placenta and enter fetal circulation. No evidence of embryo or fetotoxicity or teratogenicity has been shown in studies with pregnant rats and rabbits. In rats receiving aztreonam for injection during late gestation and lactation, no drug induced changes in maternal, fetal or neonatal parameters were observed. These animal reproduction and developmental toxicity studies used parenteral routes of administration that would provide systemic exposures far in excess of the average peak plasma levels measured in humans following Cayston therapy.

No adequate and well-controlled studies of aztreonam for injection or Cayston in pregnant women have been conducted. Because animal reproduction studies are not always predictive of human response, Cayston should be used during pregnancy only if clearly needed.

Nursing Mothers

Following administration of aztreonam for injection, aztreonam is excreted in human milk at concentrations that are less than one percent of those determined in simultaneously obtained maternal serum. Peak plasma concentrations of aztreonam following administration of Cayston (75 mg) are approximately 1% of peak concentrations observed following IV aztreonam (500 mg). Therefore, use of Cayston during breastfeeding is unlikely to pose a risk to infants.

Pediatric Use

Patients 7 years and older were included in clinical trials with Cayston. Fifty-five patients under 18 years of age received Cayston in placebo-controlled trials. No dose adjustments were made for pediatric patients. Pyrexia was more commonly reported in pediatric patients than in adult patients. Safety and effectiveness in pediatric patients below the age of 7 years have not been established.

Geriatric Use

Clinical trials of Cayston did not include Cayston-treated patients aged 65 years of age and older to determine whether they respond differently from younger patients.

Use in Patients with Renal Impairment

Aztreonam is known to be excreted by the kidney. Placebo-controlled clinical trials with Cayston excluded patients with abnormal baseline renal function (defined as serum creatinine greater than 2 times the upper limit of normal range). Given the low systemic exposure of aztreonam following administration of Cayston, clinically relevant accumulation of aztreonam is unlikely to occur in patients with renal impairment. Therefore, Cayston may be administered to patients with mild, moderate and severe renal impairment with no dosage adjustment.

Overdosage

No overdoses have been reported with Cayston in clinical trials to date. In clinical trials, 225 mg doses of Cayston via inhalation were associated with higher rates of drug-related respiratory adverse reactions, particularly cough. Since the peak plasma concentration of aztreonam following administration of Cayston (75 mg) is approximately 0.6 mcg/mL, compared to a serum concentration of 54 mcg/mL following administration of aztreonam for injection (500 mg), no systemic safety issues associated with Cayston overdose are anticipated.

Cayston Description

A dose of Cayston consists of a 2 mL amber glass vial containing lyophilized aztreonam (75 mg) and lysine (46.7 mg), and a low-density polyethylene ampule containing 1 mL sterile diluent (0.17% sodium chloride). The reconstituted solution is for inhalation. The formulation contains no preservatives or arginine.

The active ingredient in Cayston is aztreonam, a monobactam antibacterial. The monobactams are structurally different from beta-lactam antibiotics (e.g., penicillins, cephalosporins, carbapenems) due to a monocyclic nucleus. This nucleus contains several side chains; sulfonic acid in the 1-position activates the nucleus, an aminothiazolyl oxime side chain in the 3-position confers specificity for aerobic Gram-negative bacteria including Pseudomonas spp., and a methyl group in the 4-position enhances beta-lactamase stability.

Aztreonam is designated chemically as (Z) - 2 - [[[(2 - amino - 4 - thiazolyl)[[(2S,3S) - 2 - methyl - 4 - oxo - 1 - sulfo - 3 - azetidinyl]carbamoyl]methylene]amino]oxy] - 2 - methylpropionic acid. The structural formula is presented below:

Cayston is a white to off-white powder. Cayston is sterile, hygroscopic, and light sensitive. Once reconstituted with the supplied diluent, the pH range is 4.5 to 6.0.

Cayston - Clinical Pharmacology

Mechanism of Action

Aztreonam is an antibacterial drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

Sputum Concentrations

Sputum aztreonam concentrations exhibited considerable variability between patients receiving Cayston (75 mg) in clinical trials. The mean sputum concentration 10 minutes following the first dose of Cayston (n = 195 patients with CF) was 726 mcg/g. Mean sputum concentrations of aztreonam in patients receiving Cayston 3 times a day for 28 days were 984 mcg/g, 793 mcg/g, and 715 mcg/g 10 minutes after dose administration on Days 0, 14, and 28, respectively, indicating no accumulation of aztreonam in sputum.

Plasma Concentrations

Plasma aztreonam concentrations exhibited considerable variability between patients receiving Cayston (75 mg) in the clinical trials. The mean plasma concentration one hour following the first dose of Cayston (at approximately the peak plasma concentration) was 0.59 mcg/mL. Mean peak plasma concentrations in patients receiving Cayston 3 times a day for 28 days were 0.55 mcg/mL, 0.67 mcg/mL, and 0.65 mcg/mL on Days 0, 14, and 28, respectively, indicating no systemic accumulation of aztreonam. In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 mcg/mL.

Absorption

Evaluation of plasma and urine aztreonam concentrations following administration of Cayston indicates low systemic absorption of aztreonam. Approximately 10% of the total Cayston dose is excreted in the urine as unchanged drug, as compared to 60–65% following intravenous administration of aztreonam for injection.

Distribution

The protein binding of aztreonam in serum is approximately 56% and is independent of dose.

Metabolism

Following intramuscular administration of aztreonam for injection 500 mg every 8 hours for 7 days, approximately 6% of the dose was excreted as a microbiologically inactive open β-lactam ring hydrolysis product in an 8-hour urine collection on the last day of multiple dosing.

Excretion

The elimination half-life of aztreonam from plasma is approximately 2.1 hours following administration of Cayston to adult patients with CF, similar to what has been reported for aztreonam for injection. Approximately 10% of the total Cayston dose is excreted in the urine as unchanged drug. Systemically absorbed aztreonam is eliminated about equally by active tubular secretion and glomerular filtration. Following administration of a single intravenous dose of radiolabeled aztreonam for injection, about 12% of the dose was recovered in the feces.

Microbiology

Mechanism of Action

Aztreonam exhibits activity in vitro against Gram-negative aerobic pathogens including P. aeruginosa. Aztreonam binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis and death of the cell. Aztreonam activity is not decreased in the presence of CF lung secretions.

Susceptibility Testing

A single sputum sample from a patient with CF may contain multiple morphotypes of P. aeruginosa and each morphotype may have a different level of in vitro susceptibility to aztreonam. There are no in vitro susceptibility test interpretive criteria for isolates of P. aeruginosa obtained from the sputum of CF patients.1

Development of Resistance

No changes in the susceptibility of P. aeruginosa to aztreonam were observed following a 28-day course of Cayston in the placebo-controlled trials.

Cross-Resistance

No cross-resistance to other classes of antibiotics, including aminoglycosides, quinolones, and beta-lactams, was observed following a 28-day course of Cayston in the Phase 3 placebo-controlled trials or in an open-label follow-on trial of up to nine 28-day courses of 75 mg Cayston 3 times a day.

Other

No trends in the treatment-emergent isolation of other bacterial respiratory pathogens (Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus) were observed in clinical trials. There was a slight increase in the isolation of Candida spp. following up to nine 28-day courses of Cayston therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of aztreonam demonstrated no drug-related increase in the incidence of tumors. Rats were exposed to aztreonam for up to 4 hours per day. Peak plasma levels of aztreonam averaging approximately 6.8 mcg/mL were measured in rats at the highest dose level. This is approximately 12-fold higher than the average peak plasma level measured in humans following Cayston therapy.

Genetic toxicology studies performed in vitro demonstrated that aztreonam did not induce structural chromosome aberrations in CHO cells and did not induce mutations at the TK locus in mouse lymphoma L5178Y TK+/- cells. Likewise, genetic toxicology studies performed in vivo did not reveal evidence of mutagenic potential.

Aztreonam did not impair the fertility of rats when administered at doses that would provide systemic exposures far in excess of peak plasma levels measured in humans following Cayston therapy.

Clinical Studies

Cayston was evaluated over a period of 28 days of treatment in a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients with CF and P. aeruginosa. This trial was designed to evaluate improvement in respiratory symptoms. Patients 7 years of age and older and with FEV1 of 25% to 75% predicted were enrolled. All patients received Cayston or placebo on an outpatient basis administered with the Altera Nebulizer System. All patients were required to take a dose of an inhaled bronchodilator (beta-agonist) prior to taking a dose of Cayston or placebo. Patients were receiving standard care for CF, including drugs for obstructive airway diseases.

The trial enrolled 164 patients with CF and P. aeruginosa. The mean age was 30 years, and the mean baseline FEV1 % predicted was 55%; 43% were females and 96% were Caucasian. These patients were randomized in a 1:1 ratio to receive either Cayston (75 mg) or volume-matched placebo administered by inhalation 3 times a day for 28 days. Patients were required to have been off antibiotics for at least 28 days before treatment with study drug. The primary efficacy endpoint was improvement in respiratory symptoms on the last day of treatment with Cayston or placebo. Respiratory symptoms were also assessed two weeks after the completion of treatment with Cayston or placebo. Changes in respiratory symptoms were assessed using a questionnaire that asks patients to report on symptoms like cough, wheezing, and sputum production.

Improvement in respiratory symptoms was noted for Cayston-treated patients relative to placebo-treated patients on the last day of drug treatment. Statistically significant improvements were seen in both adult and pediatric patients, but were substantially smaller in adult patients. Two weeks after completion of treatment, a difference in respiratory symptoms between treatment groups was still present, though the difference was smaller.

Pulmonary function, as measured by FEV1 (L), increased from baseline in patients treated with Cayston (see Figure 1). The treatment difference at Day 28 between Cayston-treated and placebo-treated patients for percent change in FEV1 (L) was statistically significant at 10% (95% CI: 6%, 14%). Improvements in FEV1 were comparable between adult and pediatric patients. Two weeks after completion of drug treatment, the difference in FEV1 between Cayston and placebo groups had decreased to 6% (95% CI: 2%, 9%).

Figure 1. Adjusted Mean Percent Change in FEV1 from Baseline to Study End (Days 0–42).

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Eighth Edition; Approved Standard. CLSI Document M7-A8. CLSI, Wayne, PA 19087. January, 2009.

How Supplied/Storage and Handling

Each kit for a 28-day course of Cayston contains 84 sterile vials of Cayston and 88 ampules of sterile diluent packed in 2 cartons, each carton containing a 14-day supply. The four additional diluent ampules are provided in case of spillage.

Package Configuration	Dosage Strength	NDC No.
28-Day Kit	75 mg	61958-0901-1

Cayston vials and diluent ampules should be stored in the refrigerator at 2 °C to 8 °C (36 °F to 46 °F) until needed. Once removed from the refrigerator, Cayston and diluent may be stored at room temperature (up to 25 °C/77 °F) for up to 28 days. Do not separate the Cayston vials from the diluent ampules. Cayston should be protected from light.

Do not use Cayston if it has been stored at room temperature for more than 28 days. Do not use Cayston beyond the expiration date stamped on the vial. Do not use diluent beyond the expiration date embossed on the ampule.

Cayston should be used immediately upon reconstitution. Do not reconstitute more than one dose at a time.

Do not use diluent or reconstituted Cayston if it is cloudy or if there are particles in the solution.

Patient Counseling Information

See FDA-Approved Patient Labeling

Patients should be advised that Cayston is for inhalation use only and that Cayston should only be administered using the Altera Nebulizer System. Patients should be instructed only to reconstitute Cayston with the provided diluent and not mix other drugs with Cayston in the Altera Nebulizer System.

Patients should be advised to complete the full 28-day course of Cayston even if they are feeling better. Inform the patient that if they miss a dose, they should take all 3 daily doses as long as the doses are at least 4 hours apart.

Patients should be advised to use a bronchodilator prior to administration of Cayston. Patients taking several inhaled medications should be advised to use the medications in the following order of administration: bronchodilator, mucolytics, and lastly, Cayston.

Patients should be advised to tell their doctor if they have new or worsening symptoms. Patients who believe they are experiencing an allergic reaction to Cayston should be advised to contact their doctor immediately.

Patients should be counseled that antibacterial drugs including Cayston should only be used to treat bacterial infections. They do not treat viral infection (e.g., the common cold). When Cayston is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cayston or other antibacterial drugs in the future.

Manufactured by: Gilead Sciences, Inc., Foster City, CA 94404

Cayston is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.

© 2010 Gilead Sciences, Inc. All rights reserved.

50-814-GS-000

FDA-Approved Patient Labeling

Patient Information

Cayston® (kay-stun)

(aztreonam for inhalation solution)

Read this Patient Information before you start taking Cayston and each time you get a refill. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is Cayston?

Cayston is a prescription inhaled antibiotic. Cayston is used to improve breathing symptoms in people with cystic fibrosis (CF) who have Pseudomonas aeruginosa (P. aeruginosa) in their lungs.

Cayston is only for infections caused by bacteria. It is not for infections caused by viruses, such as the common cold.

Cayston is used only with the Altera® Nebulizer System.

It is not known if Cayston is safe and effective in children under the age of 7.

Who should not take Cayston?

Do not take Cayston if you are allergic to aztreonam (AZACTAM®).

What should I tell my doctor before taking Cayston?

Before taking Cayston, tell your doctor if you:

• are allergic to any antibiotics.


• are pregnant or plan to become pregnant.


• are breast-feeding or plan to breast feed. Talk to your doctor about the best way to breast feed your baby if you take Cayston.

Tell your doctor about all the medicine you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Cayston?

• Take Cayston exactly as prescribed by your doctor.


• The dose of Cayston for both adults and children 7 years of age and older is one vial of Cayston, mixed with one ampule of saline (diluent) 3 times a day.


• Doses of Cayston should be taken at least 4 hours apart (for example: morning, after school, and before bed).


• Cayston should be taken for 28 days.


• Cayston is taken as a breathing treatment (inhalation) with the Altera Nebulizer System. Do not use any other nebulizer for your Cayston treatment.


• You should use an inhaled bronchodilator (a type of medicine used to relax and open your airways) before taking a dose of Cayston. If you do not have an inhaled bronchodilator, ask your doctor to prescribe one for you.


• If you are taking several medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments in this order:
  

  1)

  
  

  bronchodilator

  
  

  2)

  
  

  mucolytics (medicines to help clear mucus from your lungs)

  
  

  3)

  
  

  Cayston

  
  



• You should take Cayston as prescribed, in courses of 28 days on Cayston, followed by at least 28 days off Cayston, as directed by your doctor.


• Do not mix Cayston with any other medicines in your Altera Nebulizer System.


• Do not mix Cayston with the saline until right before you are ready to use it. Do not mix more than one dose of Cayston at a time.


• Each treatment should take about 2 to 3 minutes.


• If you miss a dose of Cayston, you can still take all 3 daily doses as long as they are at least 4 hours apart.


• It is important for you to finish taking the full 28-day course of Cayston even if you are feeling better. If you skip doses or do not finish the full 28-day course of Cayston, your infection may not be fully treated and Cayston may not work as well as a treatment for infections in the future.


• See the end of this Patient Information leaflet for the Patient Instructions for Use on how to take Cayston the right way.

What are the possible side effects of Cayston?

Cayston can cause serious side effects, including:

• Severe allergic reactions. Stop your treatment with Cayston and call your doctor right away if you have any symptoms of an allergic reaction, including:
  
  • Rash or swelling of your face
  
  
  • Throat tightness
  
  


• Trouble breathing right after treatment with Cayston (bronchospasm). To decrease the chance of this happening, be sure to use your inhaled bronchodilator medicine before each treatment with Cayston. See "How should I take Cayston?"

Common side effects of Cayston include:

• Cough


• Nasal congestion


• Wheezing


• Sore throat


• Fever. Fever may be more common in children than in adults.


• Chest discomfort


• Stomach area (abdominal) pain


• Vomiting

Tell your doctor if you have any new or worsening symptoms while taking Cayston. Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Cayston. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Cayston?

• Each Cayston kit contains enough vials of Cayston and ampules of saline for 28 days of treatment. There are 4 extra saline ampules in case some saline spills.


• Always keep your Cayston and saline together.


• Store Cayston and saline in the refrigerator at 36 °F to 46 °F (2 °C to 8 °C) until needed.


• When you remove Cayston and saline from the refrigerator, they may be stored at room temperature (less than 77 °F) for up to 28 days. Do not use any Cayston that has been stored at room temperature for more than 28 days.


• Keep Cayston away from light.


• Do not use Cayston after the expiration date on the vial. Do not use the saline after the expiration date on the ampule.

Keep Cayston and all medicines out of the reach of children.

General information about Cayston

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Cayston for a condition for which it was not prescribed. Do not give Cayston to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Cayston. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Cayston that is written for health professionals.

For more information, call 1-877-7Cayston (1-877-722-9786).

What are the ingredients in Cayston?

Active ingredient: aztreonam

Inactive ingredient: sodium chloride (diluent)

 

Patient Instructions for Use

Cayston®

(aztreonam for inhalation solution)

Be sure that you read, understand and follow the Patient Instructions for Use below for the right way to take Cayston. If you have any questions, ask your doctor or pharmacist.

You will need the following supplies (Figure 1):

• 1 amber colored Cayston vial


• 1 ampule of saline (diluent)


• Altera Nebulizer System

Check to make sure that your Altera Nebulizer System works properly before starting your treatment with Cayston. See the manufacturer's instructions for use that comes with your Altera Nebulizer System. This should have complete information about how to put together (assemble), prepare, use, and care for your Altera Nebulizer System.

Step 1 Preparing your Cayston for inhalation

1.

Mix (reconstitute) Cayston with the saline only when ready to take a dose. Take one amber vial of Cayston and one ampule of saline from the carton. Separate the saline ampules by gently pulling apart.

2.

Look at the ampule of saline. If it looks cloudy do not use it. Throw away this ampule and get another ampule of saline.

3.

Gently tap the vial so that the powder settles to the bottom of the vial. This helps you get the proper dose of medicine. Open the amber drug vial by lifting up the metal flap on the top (Figure 2) and pulling down (Figure 3) to carefully remove the entire metal ring from the vial (Figure 4). Safely dispose of the ring in household garbage. Carefully remove the rubber stopper.

4.

Open the ampule of saline by twisting off the tip. Squeeze out the contents completely into the vial (Figure 5). Next, close the vial with the rubber stopper and gently swirl the vial until the powder has completely dissolved and the liquid is clear.

5.

After mixing Cayston with the saline, check to make sure the diluted medicine is clear. If it is cloudy or has particles in it, do not use this medicine. Throw away this dose of medicine and start over again with a new vial of Cayston and a new ampule of saline.

6.

Use Cayston right away after you mix with the saline.

Step 2 Taking your Cayston treatment

See the manufacturer's instructions for use that comes with your Altera Nebulizer System for complete instructions on taking a treatment, and how to clean and disinfect your Altera Nebulizer Handset.

7.

Make sure the handset is on a flat, stable surface.

8.

Remove the rubber stopper from the vial, then pour all of the mixed Cayston and saline into the Medication Reservoir of the handset (Figure 6). Be sure to completely empty the vial, gently tapping the vial against the side of the Medication Reservoir if necessary. Close the Medication Reservoir (Figure 7).

9.

Begin your treatment by sitting in a relaxed, upright position. Hold the handset level, and place the Mouthpiece in your mouth. Close your lips around the Mouthpiece (Figure 8).

10.

Breathe in and out normally (inhale and exhale) through the Mouthpiece. Avoid breathing through your nose. Continue to inhale and exhale comfortably until the treatment is finished.

11.

The empty vial, stopper and saline ampule should be disposed of in household garbage upon completion of dosing.

Manufactured by: Gilead Sciences, Inc., Foster City, CA 94404

Cayston is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.

© 2010 Gilead Sciences, Inc. All rights reserved.

50-814-GS-000

Principal Display Panel - Cayston 28 Day Carton - Representative Label

NDC 61958-0901-1

GILEAD

Cayston®

(aztreonam for

inhalation solution)

75 mg/vial

For Oral Inhalation Only

Store Refrigerated, 2 °C to 8 °C (36 °F to 46 °F)

Contains:

84 Single-Use Vials of Aztreonam for Inhalation Solution

88 Diluent Ampules of Sodium Chloride 0.17%, 1 mL

(4 extra ampules provided in case of spillage)

For use only with the Altera® Nebulizer System

28-Day Supply

Rx only

Cayston  aztreonam  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61958-0901

Packaging # NDC Package Description Multilevel Packaging 1 61958-0901-1 2 CARTON In 1 PACKAGE contains a CARTON 1 1 KIT In 1 CARTON This package is contained within the PACKAGE (61958-0901-1)

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 84 VIAL   84 mL Part 2 88 AMPULE   88 mL

Part 1 of 2 AZTREONAM  aztreonam  powder, for solution

Product Information       Route of Administration RESPIRATORY (INHALATION) DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength aztreonam (aztreonam) aztreonam 75 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength lysine monohydrate

Product Characteristics Color WHITE (white to off-white powder) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 1 mL In 1 VIAL None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050814 02/22/2010

Part 2 of 2 STERILE DILUENT  sodium chloride  solution

Product Information       Route of Administration RESPIRATORY (INHALATION) DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength No Active Ingredients Found

Inactive Ingredients Ingredient Name Strength sodium chloride 1.7 mg  in 1 mL water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 1 mL In 1 AMPULE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050814 02/22/2010

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA050814	02/22/2010

Labeler - Gilead Sciences, Inc. (185049848)

Revised: 09/2011Gilead Sciences, Inc.

More Cayston resources

• Cayston Side Effects (in more detail)
• Cayston Use in Pregnancy & Breastfeeding
• Cayston Drug Interactions
• Cayston Support Group
• 0 Reviews for Cayston - Add your own review/rating

• Cayston Advanced Consumer (Micromedex) - Includes Dosage Information


• Cayston Consumer Overview


• Cayston MedFacts Consumer Leaflet (Wolters Kluwer)


• Aztreonam Professional Patient Advice (Wolters Kluwer)


• Azactam Monograph (AHFS DI)


• Azactam Advanced Consumer (Micromedex) - Includes Dosage Information


• Azactam MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Cayston with other medications

• Cystic Fibrosis
• Pneumonia with Cystic Fibrosis

Cefa-Drops

Dosage Form: FOR ANIMAL USE ONLY
Cefa-Drops®

Cefadroxil for Oral Suspension, USP

NADA 140-684, Approved by FDA

Cefa-Drops Description

Cefa-Drops (cefadroxil) contain a semi-synthetic cephalosporin antibiotic intended for oral administration. Cefa-Drops has an orange-pineapple flavor.

Cefadroxil is a member of a group of semi-synthetic derivatives of cephalosporin C, found among the metabolic products of the fungus Cephalosporium acremonium. The cephalosporins are structurally related to the penicillins in that both contain a 4-member beta-lactam ring. Cefadroxil is a 7-amino cephalosporanic acid substituted at the 7 position to form a molecule designated chemically as (6R, 7R)-7- [(R)-2-amino-2-(p-hydroxyphenyl)acetamido]- 3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- ene-2-carboxylic acid monohydrate:

CAUTION

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

CAUTION

The enclosed dose dropper in Cefa Drops contains natural rubber latex which may cause allergic reactions.

INDICATIONS

Cefa-Drops (cefadroxil) are indicated for the treatment of the following conditions:

Dogs: Genitourinary tract infections (cystitis) caused by susceptible strains of Escherichia coli, Proteus mirabilis and Staphylococcus aureus.

Skin and soft tissue infections including cellulitis, pyoderma, dermatitis, wound infections and abscesses caused by susceptible strains of Staphylococcus aureus.

Cats: Skin and soft tissue infections including abscesses, wound infections, cellulitis and dermatitis caused by susceptible strains of Pasteurella multocida, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus spp.

DOSAGE

Dogs: Cefa-Drops, 50 mg, should be administered orally at a dosage of 10 mg/lb of body weight twice daily. Dogs with skin or soft tissue infections should be treated for a minimum of three days. Genitourinary tract infections should be treated for a minimum of seven days with cefadroxil. Maximum duration of therapy should not exceed 30 days.

Cats: Cefa-Drops, 50 mg, should be administered orally at a dosage of 10 mg/lb of body weight once daily. Maximum duration of therapy should not exceed 21 days.

In both species, drug treatment should continue for at least 48 hours after the animal is afebrile or asymptomatic. If no response is observed after three days of treatment, therapy should be discontinued and the case should be re-evaluated.

TO PREPARE SUSPENSION

Tap bottle lightly to loosen powder. For 15 mL bottle, add 10.4 mL of water in two portions. For 50 mL bottle, add 34 mL of water in two portions. Shake well after each addition. After mixing, store in refrigerator. Shake well before use. Discard unused portion after 14 days.

Droppers supplied with Cefa-Drops are calibrated in mL increments. When mixed as directed, each mL contains cefadroxil monohydrate equivalent to 50 mg cefadroxil.

Contraindications

Cefa-Drops should not be administered to dogs or cats with a known allergy to cephalosporins. In penicillin-allergic animals, Cefa-Drops should be used with caution.

Warnings

For use in dogs and cats only. Do not use in animals intended for human consumption. Safety for use in pregnant female dogs and cats or in breeding males has not been determined (see Animal Safety).

Adverse Reactions

Occasional nausea and vomiting have been reported following cefadroxil therapy. Administration with food appears to decrease nausea. Diarrhea and lethargy have been occasionally reported.

To report suspected adverse reactions, to obtain a Material Safety Data Sheet (MSDS) or for technical assistance, call 1-866-638-2226.

Cefa-Drops - Clinical Pharmacology

ACTION

Cefadroxil, like other beta-lactam antibiotics, is a bactericidal agent that causes death of bacterial cells through a diversity of biological and biochemical effects on the cell wall. The spectrum of antibacterial activity includes many gram-negative organisms since cefadroxil, like other cephalosporins, has the ability to penetrate the outer envelope of gram-negative bacilli, thereby gaining access to cell wall target sites. Cefadroxil is generally not broken down by penicillinases such as those produced by penicillin-resistant staphylococci, although cephalosporinases have been identified that can inactivate the molecule.

MICROBIOLOGY

The effectiveness of Cefa-Drops in skin and soft tissue infections caused by Staphylooccus aureus, (including penicillin-resistant strains) and in urinary tract infections caused by Staphylococcus aureus, Escherichia coli and Proteus mirabilis, has been demonstrated clinically in the dog. In cats, the effectiveness of cefadroxil in skin and soft tissue infections caused by susceptible pathogens such as Pasteurella multocida, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus spp. has also been demonstrated. In addition, cefadroxil has a broad spectrum of activity against both gram-positive and gram-negative human isolates. Although the clinical significance of in vitro data is unknown in the target species, the following human isolates are generally susceptible to cefadroxil at the indicated concentrations1.

		Minimum Inhibitory Concentration (mcg/mL)
Organism	No. of Isolates	Range	MIC90*
Streptococcus pyogenes	(24)	0.063-0.125	0.11
Streptococcus agalactiae	(27)	0.25-1	0.92
Streptococcus pneumoniae	(29)	0.5-2	1.2
Staphylococcus aureus, penicillin sensitive	(16)	2-16	3.2
Staphylococcus aureus, penicillin resistant	(63)	1-32	6.2
Staphylococcus epidermidis	(28)	0.125-4	2.13
Escherichia coli	(59)	4->125	16.0
Proteus mirabilis	(62)	4->125	15.6
Klebsiella pneumoniae	(61)	4-16	7.85
Salmonella spp.	(22)	4-8	7.19
Shigella spp.	(12)	2-8	6.98
Pasteurella multocida	(2)		1.4

*Concentration at which 90% of the isolates are susceptible.

The susceptibility of organisms to cefadroxil should be determined using the cephalosporin class disc, 30mcg. Specimens for susceptibility testing should be collected prior to the initiation of antibiotic therapy.

PHARMACOKINETICS

Cefadroxil is stable in gastric acid and only moderately bound to serum proteins (approximately 20%). Cefadroxil is well absorbed from the gastrointestinal tract even when administered with food. The drug is excreted largely unchanged by the kidney. In humans, high concentrations of cefadroxil activity are found in urine within three hours after oral dosage2. The concurrent administration of probenecid retards the elimination rate.

In dogs, oral administration of cefadroxil at a dosage of 10 mg/lb results in mean peak serum concentrations averaging 18.6 mcg/mL within 1 to 2 hours after treatment3. The serum half-life (T½) following oral administration is approximately 2 hours. Over 50%of an orally administered dose is excreted unchanged in the urine of dogs within 24 hours. Serum concentration time profiles in dogs following oral administration are illustrated graphically in Figure 1.

Figure 1: Cefadroxil Serum Concentration Curves in Dogs3

In cats, oral administration of cefadroxil at a dosage of 10 mg/lb results in mean peak serum concentrations of 17.4 mcg/mL within 1 to 2 hours after treatment. The serum half-life (T½) following oral administration to cats is 2½ to 3 hours. Serum concentration time profiles in cats following oral administration are illustrated graphically in Figure 2.

Figure 2: Cefadroxil Serum Concentration Curves in Cats

ANIMAL SAFETY

In subacute studies, dogs administered 100, 200 or 400 mg/kg/day for 13 weeks showed no consistent or distinct treatment-related histopathologic changes. In chronic toxicity studies, dogs receiving doses as high as 600 mg/kg/day for six months showed no discernible treatment-related effects, with the exception of emesis in dogs receiving a 400 mg/kg/day dose at one time. No distinct or consistent meaningful drug-related changes in the hematologic, coagulation or urinalysis test results or in histologic examination of tissues were observed when compared to controls.

No teratogenic or antifertility effects were seen in reproductive studies done in mice and rats receiving dosages as high as nine times the maximum recommended canine dosage.

In cats, oral administration of cefadroxil at a dosage of 240 mg/kg/day divided into two equal doses (ten times the recommended daily dosage) for 21 consecutive days produced no clinical chemistry, pathological or other signs of toxicity other than reduced food consumption, vomiting and diarrhea.

STORAGE

Store at 20 - 25°C (68 - 77°F), excursions permitted between 15 - 30°C (59 - 86°F).

How is Cefa-Drops Supplied

Cefa-Drops (Cefadroxil for Oral Suspension, USP) equivalent to:

NDC 0010-4700-01 – 750 mg cefadroxil per 15 mL dropper bottle

NDC 0010-4700-02 – 2500 mg cefadroxil per 50 mL dropper bottle

REFERENCES

1. Leitner, F., et al: “Comparative antibacterial spectrum of cefadroxil.” J. Antimicrob. Chemother. 10, Suppl. B, 1 (1982).

2. Harstein, A.L., et al: “Comparison of pharmacological and antimicrobial properties of cefadroxil and cephalexin.” Antimicrob. Agents Chemother. 12, 93 (1977).

3. Gingerich, D. A.: “Clinical pharmacology of the cephalosporins and their present use in veterinary medicine.” College of Veterinary Medicine Review, Mississippi State University, 2, 93 (1982).

© 2010 Boehringer Ingelheim Vetmedica, Inc. All Rights Reserved.

Cefa-Drops is a registered trademark of Boehringer Ingelheim Vetmedica, Inc.

Made in India

Manufactured for:

Boehringer Ingelheim Vetmedica, Inc.

St. Joseph, MO 64506 U.S.A.

D4230B 11660 P1503133

ML LABEL

ML CARTON

ML LABEL

ML CARTON

Cefa-Drops  cefadroxil for oral suspension  suspension

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 0010-4700 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CEFADROXIL (CEFADROXIL) CEFADROXIL 50 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0010-4700-01 10.4 mL In 1 BOTTLE None 2 0010-4700-02 34 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA140684	07/20/1988

Labeler - Boehringer Ingelheim Vetmedica, Inc. (007134091)

Revised: 12/2010Boehringer Ingelheim Vetmedica, Inc.

Loprox TS Topical

Generic Name: ciclopirox (Topical route)

sye-kloe-PIR-ox

Commonly used brand name(s)

In the U.S.

• CNL8


• Loprox


• Loprox TS


• Penlac

Available Dosage Forms:

• Lotion


• Gel/Jelly


• Cream


• Suspension


• Shampoo


• Solution


• Powder

Therapeutic Class: Antifungal

Uses For Loprox TS

Ciclopirox is used to treat infections caused by fungus. It works by killing the fungus or preventing its growth.

Ciclopirox cream, gel, or lotion are applied to the skin to treat:

• ringworm of the body (tinea corporis);


• ringworm of the foot (tinea pedis; athlete's foot);


• ringworm of the groin (tinea cruris; jock itch);


• “sun fungus” (tinea versicolor; pityriasis versicolor); and


• certain other fungus infections, such as Candida (Monilia) infections.

Ciclopirox gel or shampoo may also be applied to the scalp to treat seborrheic dermatitis.

Ciclopirox topical solution (nail lacquer) is applied to the nails to treat ringworm of the nails (tinea unguium).

Ciclopirox is available only with your doctor's prescription.

Before Using Loprox TS

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of ciclopirox in children under the age of 10 with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of ciclopirox in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of ciclopirox

This section provides information on the proper use of a number of products that contain ciclopirox. It may not be specific to Loprox TS. Please read with care.

For patients using the cream, gel, or lotion form of this medicine:

• Keep this medicine away from the eyes.


• Apply enough ciclopirox to cover the affected and surrounding skin or scalp areas and rub in gently.

For patients using the shampoo form of this medicine:

• Keep this medicine away from the eyes.


• Apply shampoo to wet hair. Lather and leave on hair and scalp for 3 minutes. A timer may be used. Rinse off.

For patients using the topical solution form of this medicine:

• Keep this medicine away from the eyes and mucous membranes


• This medicine comes with a patient instruction sheet. Read this sheet carefully and follow the directions. If you have any questions on how to use this medicine, be sure to ask your health care professional.


• In addition to daily application of this medicine, you will need to trim your nails as directed, and visit your healthcare professional at regular intervals to have the unattached infected nails removed.


• Do not use nail polish or other nail cosmetic products on the treated nails.


• Do not use near heat or open flame.

When ciclopirox is used to treat certain types of fungus infections of the skin, an occlusive dressing (airtight covering, such as kitchen plastic wrap) should not be applied over the medicine. To do so may irritate the skin. Do not apply an airtight covering over this medicine unless you have been directed to do so by your doctor.

To help clear up your infection completely, it is very important that you keep using ciclopirox for the full time of treatment , even if your symptoms begin to clear up after a few days. Since fungus infections may be very slow to clear up, you may have to continue using this medicine every day for several weeks or more. If you stop using this medicine too soon, your symptoms may return. Do not miss any doses .

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical cream and lotion dosage forms:
  
  • Fungus infections (treatment):
    
    • Adults and children 10 years of age and over—Apply two times a day, morning and evening.
    
    
    • Children up to 10 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  
  For topical gel dosage form:
  
  • Fungus infections (treatment) or seborrheic dermatitis (treatment):
    
    • Adults and children 16 years of age and over—Apply two times a day, morning and evening.
    
    
    • Children up to 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  
  For shampoo dosage form:
  
  • Seborrheic dermatitis (treatment):
    
    • Adults and children 16 years of age and over—Apply 1 teaspoon (or up to 2 teaspoons for long hair) two times a week for four weeks with at least three days between each application.
    
    
    • Children up to 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  
  For topical solution dosage form:
  
  • Fungus infections (treatment):
    
    • Adults —Apply once daily, preferably at bedtime or eight hours before washing.
    
    
    • Children up to 18 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Loprox TS

If your skin problem does not improve within 2 to 4 weeks, or if it becomes worse, check with your doctor.

Inform your doctor right away if the area where you applied the medicine shows signs of increased irritation (e.g., redness, itching, burning, blistering, swelling, or oozing) because it could be an allergic reaction.

Nail problems treated with the topical solution form of this medicine may take up to 6 months to start improving.

To help clear up your infection completely and to help make sure it does not return, good health habits are also required. The following measures will help reduce chafing and irritation and will also help keep the area cool and dry.

• For patients using ciclopirox for ringworm of the groin (tinea cruris):
  
  • Avoid wearing underwear that is tight-fitting or made from synthetic materials (for example, rayon or nylon). Instead, wear loose-fitting, cotton underwear.
  
  
  • Use a bland, absorbent powder (for example, talcum powder) or an antifungal powder (for example, tolnaftate) on the skin. It is best to use the powder between applications of ciclopirox.
  
  


• For patients using ciclopirox for ringworm of the foot (tinea pedis):
  
  • Carefully dry the feet, especially between the toes, after bathing.
  
  
  • Avoid wearing socks made from wool or synthetic materials (for example, rayon or nylon). Instead, wear clean, cotton socks and change them daily or more often if the feet sweat freely.
  
  
  • Wear sandals or well-ventilated shoes (for example, shoes with holes on top or on the side).
  
  
  • Use a bland, absorbent powder (for example, talcum powder) or an antifungal powder (for example, tolnaftate) between the toes, on the feet, and in socks and shoes freely once or twice a day. It is best to use the powder between applications of ciclopirox.
  
  

If you have any questions about these measures, check with your health care professional.

Loprox TS Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Less common - with ciclopirox shampoo

• Fainting


• fast, pounding, or irregular heartbeat or pulse


• palpitations

Rare

• Burning, itching, redness, swelling, or other signs of irritation not present before use of this medicine

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common - with ciclopirox shampoo

• Dandruff


• headache


• itching skin or scalp


• oily skin


• rash


• skin disorder

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Loprox TS Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Loprox TS Topical resources

• Loprox TS Topical Side Effects (in more detail)
• Loprox TS Topical Use in Pregnancy & Breastfeeding
• Loprox TS Topical Support Group
• 0 Reviews for Loprox TS Topical - Add your own review/rating

Compare Loprox TS Topical with other medications

• Cutaneous Candidiasis
• Seborrheic Dermatitis
• Tinea Corporis
• Tinea Cruris
• Tinea Pedis
• Tinea Versicolor

Goddards Muscle Lotion

Goddards Muscle Lotion

(turpentine oil, dilute acetic acid, dilute ammonia)

Important information about Goddards Muscle Lotion

• This medicine relieves symptoms of rheumatic and muscular pains.


• It can be used by adults, the elderly and children.

Do not use on broken skin

Now read the rest of the leaflet before you use this medicine. It includes other information which might be especially important for you.

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


• Ask your pharmacist if you need any more information or advice.


• If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

What the medicine is for

Goddards Muscle Lotion is a topical emulsion which has warming and soothing properties. It is used to relieve the symptoms of muscle pain and stiffness, including backache, sciatica, lumbago, fibrositis, rheumatic pain and pain caused by bruises, sprains, strains, stiff
muscles and unbroken chilblains.

Before you use this medicine

Do not use the medicine if you or your child have broken skin.

Pregnant or breastfeeding

Ask your doctor or pharmacist for advice before using this medicine if you are pregnant, might be pregnant or are breastfeeding. Goddards Muscle Lotion should not be used in pregnancy unless the doctor has told you to do so.

How to use this medicine

Apply it to the skin

Adults, the elderly and children

• Shake the bottle thoroughly.


• Pour enough muscle lotion into the palm of your hand and rub into the affected area until dry, once or twice a day.


• Avoid contact with eyes and sensitive areas of the skin.


• Wash hands well after use.

For external use only.

If your symptoms persist you should ask your doctor for advice.

If you swallow some

If you accidentally swallow some, see a doctor straight away. Take the pack with you to show which medicine you have swallowed.

Possible side effects

There are no known side effects from using this medicine when used as directed.

If you notice any side effects, stop use and tell your doctor or pharmacist. They will tell you what to do.

Storing this medicine

• Keep it out of the reach and sight of children.


• There are no special conditions for storing this medicine.


• Do not use after the expiry date shown on the carton. The expiry date refers to the last day of that month.


• Medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of any unused medicine. These measures will help to protect the environment.

Further information

What is in this medicine

The active ingredients are: turpentine oil 22% v/v, dilute acetic acid 30% v/v, dilute ammonia solution 14% v/v.

The other ingredients are: arlacel 83 V (sorbitan sesquioleate), PEG-8 oleate and purified water.

What the medicine looks like

Goddards Muscle Lotion is a creamy coloured emulsion which smells of turpentine and ammonia.

It is supplied in 200ml bottles.

Marketing authorisation holder

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

Manufacturer

Thornton and Ross Ltd.

Huddersfield

HD7 5QH

UK

Goddards is a trade mark of Actavis Group PTC ehf.

This leaflet was revised in March 2009