Acthrel

corticorelin ovine triflutate

Dosage Form: for Injection

DESCRIPTION:

Acthrel® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder, containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH (hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for corticorelin ovine triflutate is described below:

Ser - Gln - Glu - Pro - Pro - Ile - Ser - Leu - Asp - Leu - Thr - Phe - His - Leu - Leu - Arg - Glu - Val - Leu - Glu - Met - Thr - Lys - Ala - Asp - Gln - Leu - Ala - Gln - Gln - Ala - His - Ser - Asn - Arg - Lys - Leu - Leu - Asp - Ile - Ala - NH2•xCF3COOH

whereas x=4 - 8.

The empirical formula of corticorelin ovine is C205H339N59O63S with a molecular weight of 4670.35 Daltons.

Acthrel® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The preparation is intended for intravenous administration.

CLINICAL PHARMACOLOGY:

Pharmacodynamics:

In normal subjects, intravenous administration of corticorelin results in a rapid and sustained increase of plasma ACTH levels and a near parallel increase of plasma cortisol. In addition, intravenous administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related proopiomelanocortin peptides β- and y-lipotropins (β -and y-LPH) and 13-endorphin (β -END). A number of dose-response studies have been performed on normal subjects using a range of corticorelin doses. In one study, doses of corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers. Blood samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations. There was a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol. The threshold dose was 0.03 mcg/kg, the half maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.

Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of >0.3 mcg/kg and reached peak levels after 10-15 minutes. Plasma cortisol levels increased within 10 minutes and reached peak levels at 30 to 60 minutes. As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection. Similar results were found in another study using 0.3, 3.0, and 30 mcg/kg doses. The duration of mean plasma ACTH increase after injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively. The effect on plasma cortisol was similar, but more prolonged. Because there are differences in basal levels and peak response levels following a.m. or p.m. administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation test be carried out at the same time of day as the original evaluation.

Baseline ACTH and cortisol levels are usually higher in the morning. Pooled ACTH values from normal unstressed subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were 11 ± 3 mcg/dL in the a.m. and 4 2 mcg/dL in the p.m. The normal unstressed person has about seven to ten secretory episodes of ACTH each day. Most of them occur in the early morning hours and are responsible for the morning plasma cortisol surge. The following figure shows the daily circadian rhythm of ACTH and cortisol secretions in a normal unstressed person. Insulin, plasma renin activity, prolactin, and growth hormone release are not affected by corticorelin administration in humans.

Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increase plasma ACTH concentrations to a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours, comparable to those levels observed in patients with major depression, but less than levels noted in Cushing's disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however, continued to elicit the expected ACTH and cortisol responses.

Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.

The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin administered to normal volunteers in the morning and the evening are given below. These values were obtained by combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.

The following table is to be used only as a general guide.

Basal Concentrations and Peak Responses of ACTH and Cortisol in Normal Subjects after 1 mcg/kg or 100 mcg of Acthrel®
Time of Day	No. of Subjects	ACTH Concentration mean (range) pg/mL		Cortisol Concentration mean (range) mcg/dL
		Basal	Peak	Basal	Peak
a.m.	143	28 (16-65)	68 (39-114)	11 (8-13)	21 (17-25)
p.m.	70	9 (8-13)	30 (25-42)	4 (2-6)	16 (15-18)

Pharmacokinetics:

Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve. Plasma half-lives for IR-corticorelin are 11.6 ±1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate metabolic clearance rate of 95 ± 11 L/m2/day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound specifically by a circulating plasma protein.

INDICATIONS AND USAGE:

Acthrel® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing’s syndrome.

Differential Diagnosis:

There are two forms of Cushing’s syndrome:

1. ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing’s disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and,


2. ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas),

After the establishment of hypercortisolism consistent with the presence of Cushing’s syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion.

The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:

1. High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). Acthrel® injection (1 mcg/kg) results in:
   
   1. Increased plasma ACTH levels
   
   
   2. Increased plasma cortisol levels
   
   
   
   Diagnosis: Cushing’s disease (ACTH of pituitary origin)
   


2. High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL). Acthrel® injection (1 mcg/kg) results in:
   
   1. Little or no response of plasma ACTH levels
   
   
   2. Little or no response of plasma cortisol levels
   
   
   
   Diagnosis: Ectopic ACTH syndrome

Test Methodology:

To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood samples.

Procedure:

1. Venous blood samples should be drawn 15 minutes before and immediately prior to Acthrel® administration. The ACTH baseline is obtained by averaging the values of the two samples.


2. Administer Acthrel® as an intravenous infusion over a 30- to 60- second interval at a dose of 1mcg/kg body weight. Higher doses are not recommended (see PRECAUTIONS and ADVERSE REACTIONS).


3. Draw venous blood samples at 15, 30, and 60 minutes after administration.


4. Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. It is extremely important to recognize that the reliability of the Acthrel® test is directly related to the inter-assay and intra-assay variability of the laboratory performing the assay.

Cortisol determinations may be performed on the same blood samples for the same time points as outlined above. The blood sample handling precautions noted for ACTH should be followed for cortisol.

Interpretation of Test Results:

The interpretation of the ACTH and cortisol responses following Acthrel® administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the laboratory that performs the ACTH and cortisol assays.

Cushing’s Disease

The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing’s disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing’s disease tested with corticorelin do not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin administration has been found in Cushing’s disease patients.

Ectopic ACTH Secretion

Patients with Cushing’s syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of patients with ectopic sources of ACTH that have responded to the corticorelin test.

SUMMARY OF ACTH RESPONSES IN PATIENTS WITH HIGH BASAL CORTISOL

	High ACTH Response	Low ACTH Response
High Basal ACTH	Cushing’s Disease	Ectopic ACTH Secretion

CUSHING’S DISEASE ACTH RESPONSES
(mean of 181 patients)
Basal ACTH 63 ± 72 pg/mL (mean ± SD)
Peak ACTH 189 ± 262 pg/mL (mean ± SD)
Mean of individual change from baseline + 227%

ECTOPIC ACTH SECRETION RESPONSES
(mean for 31 patients)
Basal ACTH 266 ± 464 pg/mL (mean ± SD)
Peak ACTH 276 ± 466 pg/mL (mean ± SD)
Mean of individual change from baseline + 15%

False negative responses to the corticorelin test in Cushing’s disease patients occur approximately 5 to 10% of the time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency. (See INDICATIONS AND USAGE, Differential Diagnosis)

PRECAUTIONS:

General:

The severity of adverse effects to a corticorelin injection appear to be dose-dependent. Dosages above 1 mcg/kg are not recommended. While few adverse effects have been observed at the 1 mcg/kg or 100 mcg dose, higher doses have been associated with transient tachycardia, decreased blood pressure, loss of consciousness, and asystole (see ADVERSE REACTIONS). These symptoms can be substantially reduced by administering the drug as a 30-second intravenous infusion instead of a bolus injection. At a dose of 200 mcg corticorelin, 4 of 60 volunteers and patients with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis were reported to have had decreased blood pressures. One patient had a severe hypotensive reaction with asystole. Three other patients had an “absence-like” loss of consciousness lasting approximately 5 minutes. In subsequent investigations by the same researchers over a 3-year period using 100 mcg of corticorelin, one patient in approximately 150 to 200 experienced a severe drop in blood pressure and loss of sinus rhythm after receiving 55 mcg of corticorelin, which may have been due to interaction with heparin. (See Drug Interactions)

Drug Interactions:

The plasma ACTH response to corticorelin injection is inhibited or blunted in normal subjects pretreated with dexamethasone. The use of a heparin solution to maintain i.v. cannula patency during the corticorelin test is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration. (See ADVERSE REACTIONS)

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Animal studies have not been conducted with corticorelin to evaluate carcinogenic potential, mutagenicity, or effect on fertility.

Pregnancy (Pregnancy Category C):

Animal reproduction studies have not been conducted with corticorelin. It is also not known whether corticorelin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Acthrel® should be given to a pregnant woman only if clearly needed.

Nursing Mothers:

It is not known whether corticorelin is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Acthrel® is administered to a nursing woman.

PEDIATRIC USE:

Only a few tests have been performed on children. Dosages were1 mcg/kg body weight. Patient studies have involved only children with multiple hypothalamic and/or pituitary hormone deficiencies, or tumors. Only two studies with normal pediatric subjects have been conducted. No differences in response to the corticorelin test have been reported in the children studied.

ADVERSE REACTIONS:

Adverse effects reported with 1 mcg/kg or 100 mcg/patient include flushing of the face, neck, and upper chest (16%; 45/276), beginning almost immediately and lasting 3 to 5 minutes. Recipients have also reported an urge to take a deep breath (6%; 3/49), which occurs with a timing similar to, but less frequently than, that of flushing. Higher doses (>3mcg/kg) are associated with more prolonged flushing, tachycardia, hypotension, dyspnea, and “chest compression” or tightness. In addition, at doses of > 5 mcg/kg, significant increases in heart rate and decreases in blood pressure were observed. The cardiovascular effects occurred 2-3 minutes after injection and lasted for 30-60 minutes. The facial flushing was more prolonged, lasting up to 4 hours in some subjects. All signs and symptoms could be reduced by administering the drug as a 30-second infusion instead of by bolus injection.

Total doses of up to 200 mcg of corticorelin were administered as a bolus injection to 60 men and women, including both healthy normal subjects and patients with endocrine disorders. In most cases, only minor adverse effects, such as transient flushing and feelings of dyspnea, were noted. However, a few patients with disorders of the pituitary-adrenal axis had major symptoms. One patient had a precipitous fall in blood pressure and pulse rate and developed asystole, which required resuscitation. In two patients with Cushing’s disease and in one with secondary adrenal insufficiency, an “absence-like” loss of consciousness occurred, which started within a few seconds after injection of corticorelin and lasted from 10 seconds to 5 minutes. This was accompanied by a slight fall in blood pressure. One patient with a well documented seizure diathesis experienced a grand mal epileptic seizure following Acthrel® administration. The patient had discontinued anti-convulsant therapy the day of the procedure. (See PRECAUTIONS and Drug Interactions)

OVERDOSAGE:

Symptoms of overdose include severe facial flushing, cardiovascular changes, and dyspnea. In the event of toxic overdose ( see ADVERSE REACTIONS), adverse effects should be treated symptomatically.

DOSAGE AND ADMINISTRATION:

Dosage:

A single intravenous dose of Acthrel® at 1 mcg/kg is recommended for the testing of pituitary corticotrophin function. A dose of 1 mcg/kg is the lowest dose that produces maximal cortisol responses and significant (though apparently sub-maximal) ACTH responses. Doses above 1 mcg/kg are not recommended. (See PRECAUTIONS and ADVERSE REACTIONS)

At a dose of 1 mcg/kg, the ACTH and cortisol responses to Acthrel® are prolonged and remain elevated for up to 2 hours. The maximum increment in plasma ACTH occurs between 15 and 60 minutes after Acthrel® administration, whereas the maximum increment in plasma cortisol occurs between 30 and 120 minutes. In a clinical study of 30 normal healthy men, the peak plasma ACTH and cortisol responses to Acthrel® administration in the early afternoon occurred at 42 ± 29 minutes and 65 ± 26 minutes (average ± SD), respectively. If a repeated evaluation using the corticorelin stimulation test with Acthrel® is needed, it is recommended that the repeat test be carried out at the same time of day as the original test because there are differences in basal levels and peak response levels following a.m. or p.m. administration to normal humans.

Administration:

Acthrel® is to be reconstituted aseptically with 2 mL of Sodium Chloride injection, USP (0.9% sodium chloride), at the time of use by injecting 2 mL of the saline diluent into the lyophilized drug product cake. To avoid bubble formation, DO NOT SHAKE the vial; instead, roll the vial to dissolve the product. The sterile solution containing 50 mcg corticorelin/mL is then ready for injection by the intravenous route. The dosage to be administered is determined by the patient’s weight (1 mcg corticorelin/kg). Some of the adverse effects can be reduced by administering the drug as an infusion over 30 seconds instead of as a bolus injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED:

Acthrel® is supplied as a sterile, monpyrogenic, lyophilized, white cake containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The package provides a single-dose, rubber-capped, 5 mL, brown-glass vial (NDC 55566-0302-1) containing 100 mcg corticorelin ovine (as the trifluoroacetate). Acthrel® is stable in the lyophilized form when stored refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. The reconstituted solution is stable up to 8 hours under refrigerated conditions. Discard unused reconstituted solution.

Manufactured for:

Ferring Pharmaceuticals, Inc.

Suffern, New York 10901

By: Ben Venue Laboratories, Inc.

Bedford, OH 44146 

Rx only

03/03 6011-03

Acthrel  corticorelin ovine triflutate  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 55566-0302 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength CORTICORELIN OVINE triflutate (CORTICORELIN OVINE) Active 100 MICROGRAM  In 2 MILLILITER ASCORBIC ACID Inactive 0.88 MILLIGRAM  In 2 MILLILITER lactose Inactive 10 MILLIGRAM  In 2 MILLILITER cysteine hydrochloride monohydrate Inactive 26 MILLIGRAM  In 2 MILLILITER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 55566-0302-1 2 mL (MILLILITER) In 1 VIAL, SINGLE-DOSE None

Revised: 07/2006Ferring Pharmaceuticals, Inc.

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• Cushing's Syndrome

Paclitaxel 6 mg / ml concentrate for solution for infusion (Hospira UK Ltd)

1. Name Of The Medicinal Product

Paclitaxel 6 mg/ml concentrate for solution for infusion

2. Qualitative And Quantitative Composition

1 ml of concentrate for solution for infusion contains 6 mg paclitaxel.

Each 5 ml vial contains 30 mg of paclitaxel

Each 16.7 ml vial contains 100 mg of paclitaxel

Each 25 ml vial contains 150 mg of paclitaxel

Each 50 ml vial contains 300 mg of paclitaxel

For excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion

A clear, colourless to slightly yellow, viscous solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Ovarian cancer:

In first line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of patients with advanced disease or a residual disease (> 1cm) after initial laparotamy, in combination with cisplatin.

In second-line chemotherapy of ovarian cancer, paclitaxel is indicated in the treatment of metastatic carcinoma of the ovary after failure of standard platinum based therapy.

Breast cancer:

In the adjuvant setting, paclitaxel is indicated for the treatment of patients with node-positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with paclitaxel should be regarded as an alternative to extended AC therapy.

Paclitaxel is indicated for the initial treatment of locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is suitable, or in combination with trastuzumab, in patients who over-express human epidermal growth factor receptor 2 (HER-2) at a 3+ level as determined by immunohistochemistry and for whom an anthracycline is not suitable (see section 4.4 and 5.1)

As a single agent, treatment of metastatic carcinoma of the breast in patients who have failed to respond adequately to standard treatment with anthracyclines or in whom anthracycline therapy has not been appropriate.

Advanced non-small cell lung cancer (NSCLC):

Paclitaxel, in combination with cisplatin, is indicated for the treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgical intervention and/or radiation therapy.

AIDS-related Kaposi's sarcoma (KS):

Paclitaxel is indicated for the treatment of patients with advanced AIDS-related Kaposi's sarcoma who have failed prior liposomal anthracycline therapy.

Limited efficacy data supports this indication; a summary of the relevant studies is shown in section 5.1.

4.2 Posology And Method Of Administration

Pre-medication: All patients must be given pre-medication consisting of corticosteroids, antihistamines and H₂-receptor antagonists prior to paclitaxel administration, in order to prevent severe hypersensitivity reactions. Such pre-medication may consist of:

Table 1: Pre-medication Schedule

Pre-medication	Dose	Administration Prior to Paclitaxel
Dexamethasone	20 mg oral* or IV**	Oral: Approx. 12 and 6 hours IV: 30 – 60 min
Diphenhydramine ***	50 mg IV	30 to 60 min
Cimetidine or Ranitidine	300 mg IV 50 mg IV	30 to 60 min

* 8-20 mg for KS patients

** intravenous

*** or an equivalent antihistamine e.g. chlorphenamine 10 mg IV, administered 30 to 60 minutes prior to paclitaxel

Paclitaxel should be administered using an in-line filter with a microporous membrane of

Given the possibility of extravasation, it is advisable to monitor closely the infusion site for possible infiltration during administration

First-line treatment of ovarian cancer: Although alternative medication regimens for paclitaxel are under investigation at present, a combination therapy of paclitaxel and cisplatin is recommended.

Depending on the duration of infusion, two different dosages are recommended for paclitaxel treatment: 175 mg/m² of paclitaxel is administered as an intravenous infusion over a period of three hours followed thereafter by 75 mg/m² of cisplatin and the therapy is repeated at 3-week intervals, or 135 mg/m² of paclitaxel is administered as an intravenous infusion over a period of 24 hours followed thereafter by 75 mg/m² of cisplatin and the therapy is repeated at 3-week intervals (see section 5.1).

Second-line treatment of ovarian cancer: The recommended dose of paclitaxel is 175 mg/m² administered over 3 hours, with a 3-week interval between courses.

Adjuvant chemotherapy in breast carcinoma: the recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.

First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m²), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses (see 4.5 and 5.1).

When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Second-line chemotherapy of breast carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, with a 3-week interval between courses.

Advanced non-small cell lung cancer: The recommended dose of paclitaxel is 175 mg/m² administered over 3 hours followed by 80 mg/m² of cisplatin, with a 3-week interval between courses.

Treatment of AIDS-related KS: The recommended dose of paclitaxel is 100 mg/m² administered as a 3-hour intravenous infusion every two weeks.

Dose adjustment: Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Paclitaxel should not be re-administered until the neutrophil count is ⁹/l (⁹/l for KS patients) and the platelet count is ⁹/l (⁹/l for KS patients).

Patients who experience severe neutropenia (neutrophil count <0.5 x 10⁹/l for a minimum of 7 days) or severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (25% for KS patients) (see section 4.4).

Patients with hepatic impairment: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see section 4.4 and 5.2). Paclitaxel is not recommended in patients with severely impaired hepatic function.

4.3 Contraindications

Paclitaxel is contraindicated in patients with severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil) (see section 4.4) or to any of the excipients.

Paclitaxel is contraindicated during pregnancy and lactation (see section 4.6).

Paclitaxel should not be used in patients with baseline neutrophils <1.5 x 10⁹/l (<1 x 10⁹/l for KS patients) or platelets <100 x 10⁹/l (<75 x 10⁹/l for KS patients).

In KS, paclitaxel is also contraindicated in patients with concurrent, serious, uncontrolled infections.

4.4 Special Warnings And Precautions For Use

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer cytotoxic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available.

Patients must be pretreated with corticosteroids, antihistamines and H₂ antagonists (section 4.2).

Paclitaxel should be given before cisplatin when used in combination (section 4.5).

Significant hypersensitivity reactions: As characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in <1% of patients receiving paclitaxel after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be rechallenged with paclitaxel. Macrogolglycerol ricinoleate (polyoxyl castor oil), an excipient in this medicinal product, can cause these reactions.

Bone marrow suppression: (Primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until the neutrophil count is ⁹/l (⁹/l for KS patients) and the platelets recover to ⁹/l (⁹/l for KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF).

Severe cardiac conduction abnormalities: Have been reported rarely. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Hypotension, hypertension, and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital signs monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with non-small cell lung cancer than in those with breast or ovarian carcinoma. A single case of heart failure related to paclitaxel was seen in the AIDS-KS clinical study.

When paclitaxel is used in combination with doxorubicin or trastuzumab for initial treatment of metastatic breast cancer, attention should be placed on the monitoring of cardiac function. When patient are candidates for treatment with paclitaxel in this combination, they should undergo baseline cardiac assessment including history, physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m²) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles).

Peripheral neuropathy: The occurrence of peripheral neuropathy is frequent; the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) is recommended for all subsequent courses of paclitaxel. In non-small cell lung cancer patients the administration of paclitaxel in combination with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of single agent paclitaxel. In first-line ovarian cancer patients, administration of paclitaxel as a 3-hour infusion combined with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of a combination of cyclophosphamide and cisplatin.

Impaired hepatic function: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. No data are available for patients with severe baseline cholestasis. When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression (see section 4.2). Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see section 5.2). Paclitaxel is not recommended in patients with severely impaired hepatic function.

Since paclitaxel contains ethanol (396 mg/ml), consideration should be given to possible central nervous system and other effects. The amount of alcohol in this medicinal product may alter the effects of other medicines.

Special care should be taken to avoid intra-arterial administration of paclitaxel. In animal studies investigating local tolerance, severe tissue reactions occurred following intra-arterial administration.

Pseudomembranous colitis: Has also been reported, rarely, including cases in patients who have not received concurrent antibiotic treatment. This reaction should be considered in the differential diagnosis of severe or persistent cases of diarrhea occurring during or shortly after treatment with paclitaxel.

A combination of pulmonary radiotherapy and paclitaxel treatment (irrespective of the order of the treatments) may promote the development of interstitial pneumonitis.

Paclitaxel has been shown to be a teratogen, embryotoxic and a mutagen in several experimental systems. Therefore female and male patients of reproductive age must take contraceptive measures for themselves and/or their sexual partners during and for at least 6 months after therapy (see section 4.6). Male patients are advised to seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with paclitaxel.

In KS patients, severe mucositis is rare. If severe reactions occur, the paclitaxel dose should be reduced by 25%.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paclitaxel clearance is not affected by cimetidine premedication.

Cisplatin: Paclitaxel is recommended to be administered before cisplatin. When given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single agent use. Administration of paclitaxel after cisplatin treatment leads to greater myelosuppression and about a 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.

Doxorubicin: Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see 5.2).

Active substances metabolised in the liver:Caution should be exercised during concurrent administration of active substances which are metabolised in the liver as such active substances may inhibit the metabolism of paclitaxel. The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 (CYP450) isoenzymes CYP2C8 and 3A4 (see section 5.2). Clinical studies have demonstrated that CYP2C8-mediated metabolism of paclitaxel, (to 6α-hydroxypaclitaxel) is the major metabolic pathway in humans. Based on current knowledge, clinically relevant interactions between paclitaxel and other CYP2C8 substrates are not anticipated. Concurrent administration of ketoconazole(a known potent inhibitor of CYP3A4) does not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of interactions between paclitaxel and other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or 3A4.

Studies in KS patients, who were taking multiple concomitant medications, suggest that the systemic clearance of paclitaxel was significantly lower in the presence of nelfinavir and ritonavir, but not with indinavir. Insufficient information is available on interactions with other protease inhibitors. Consequently, paclitaxel should be administered with caution in patients receiving protease inhibitors as concomitant therapy.

4.6 Pregnancy And Lactation

There are no adequate data from the use of paclitaxel in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3) and paclitaxel is suspected to cause serious birth defects when administered during pregnancy.

As with other cytotoxic drugs, paclitaxel may cause fetal harm, and is therefore contraindicated during pregnancy.

Women should be advised to avoid becoming pregnant during therapy with paclitaxel, and to inform the treating physician immediately should this occur (see section 4.4).

It is not known whether paclitaxel is excreted in human milk. Paclitaxel is contraindicated during lactation. Breast-feeding should be discontinued for the duration of therapy with paclitaxel (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

This medicinal product contains alcohol, which may impair the ability to drive or operate machines.

4.8 Undesirable Effects

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. As the KS population is very specific, a special chapter based on a clinical study with 107 patients, is presented at the end of this section.

The frequency and severity of undesirable effects, unless otherwise mentioned, are generally similar between patients receiving paclitaxel for the treatment of ovarian carcinoma, breast carcinoma, or NSCLC. None of the observed toxicities were clearly influenced by age.

The most frequent significant undesirable effect was bone marrow suppression. Severe neutropenia (<0.5 x 10⁹/l) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for ⁹/l at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb <8.1 g/dl) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.

Neurotoxicity, mainly peripheral neuropathy, appeared to be more frequent and severe with a 175 mg/m² 3-hour infusion (85% neurotoxicity, 15% severe) than with a 135 mg/m² 24-hour infusion (25% peripheral neuropathy, 3% severe) when paclitaxel was combined with cisplatin. In NSCLC patients and in ovarian cancer patients treated with paclitaxel over 3 hours followed by cisplatin, there is an apparent increase in the incidence of severe neurotoxicity. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in a few cases. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.

Arthralgia or myalgia affected 60% of patients and was severe in 13% of patients.

A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (< 1%) of patients. Thirty-four percent of patients (17% of all courses) experienced minor hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of paclitaxel therapy.

Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e. “recall”, has been reported rarely. A specific treatment for extravasation reactions is unknown at this time.

The table below lists undesirable effects regardless of severity associated with the administration of single agent paclitaxel administered as a three hour infusion in the metastatic setting (812 patients treated in clinical studies) and as reported in the postmarketing surveillance* of paclitaxel.

The frequency of undesirable effects listed below is defined using the following convention: Very common (

Infections and infestations:	Very common: Infection   Uncommon: Septic shock   Rare*: Pneumonia, sepsis
Blood and the lymphatic system disorders:	Very common: Myelosuppression, neutropenia, anaemia, thrombocytopenia, leucopenia   Rare: Febrile neutropenia   Very rare*: Acute myeloid leukaemia, myelodysplastic syndrome
Immune system disorders:	Very common: Minor hypersensitivity reactions (mainly flushing and rash)   Uncommon: Significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress, generalised urticaria, chills and back pains)   Rare*: Anaphylactic reactions   Very rare*: Anaphylatic shock
Metabolism and nutrition disorders:	Very rare*: Anorexia
Psychiatric disorders:	Very rare*: Confusional stage
Nervous system disorders:	Very common: Neurotoxicity (mainly: peripheral neuropathy)   Rare*: Motor neuropathy (with resultant minor distal weakness)   Very rare* : Autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia
Eye disorders:	Very rare*: Optic nerve and/or visual disturbances (scintillating scotomata), particularly in patients who have received higher doses than recommended
Ear and labyrinth disorders:	Very rare*: Ototoxicity, hearing loss, tinnitus, vertigo
Cardiac disorders:	Common: Bradycardia   Uncommon: Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrio-ventricular block and syncope, myocardial infarction   Very rare*: Atrial fibrillation, supraventricular tackycardia
Vascular disorders:	Very common: Hypotension   Uncommon: Hypertension, thrombosis, thrombophlebitis   Very rare*: Shock
Respiratory, thoracic and mediastinal disorders:	Rare*: Dyspnoea, pleural effusion, interstitial pneumonia, lung fibrosis, pulmonary embolism, respiratory failure   Very rare*: Cough
Gastrointestinal disorders:	Very common: Nausea, vomiting, diarrhoea, mucosal inflammation   Very rare*: Bowel obstruction, bowel perforation, ischaemic colitis, mesenteric thrombosis, pseudomembranous colitis, oesophagitis, constipation, ascites, pancreatitis
Hepato-biliary disorders:	Very rare*: Hepatic necrosis, hepatic encephalopathy
Skin and subcutaneous tissue disorders:	Very common: Alopecia   Common: Transient and mild nail and skin changes   Rare*: Pruritus, rash, erythema   Very rare*: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)
Musculoskeletal, connective tissue and bone disorders :	Very common: Arthralgia, myalgia
General disorders and administration site conditions:	Common: Injection site reactions (including localised oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis)   Rare*: Asthenia, pyrexia, dehydration, oedema
Investigations:	Common: Severe elevation in aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)), severe elevation in alkaline phosphatase   Uncommon: Severe elevation in bilirubin   Rare*: Increase in blood creatinine

Breast cancer patients who received paclitaxel in the adjuvant setting following AC experienced more neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting and diarrhoea than patients who received AC alone. However, the frequency of these events was consistent with the use of single agent paclitaxel, as reported above.

Combination treatment

The following discussion refers to two major trials for the first-line chemotherapy of ovarian carcinoma (paclitaxel + cisplatin: over 1050 patients); two phase III trials in the first line treatment of metastatic breast cancer: one investigating the combination with doxorubicin (paclitaxel + doxorubicin: 267 patients), and another investigating the combination with trastuzumab (planned subgroup analysis, paclitaxel + trastuzumab: 188 patients) and two phase III trials for the treatment of advanced NSCLC (paclitaxel + cisplatin: over 360 patients) (see section 5.1).

When administered as a three hour infusion for the first-line chemotherapy of ovarian cancer, neurotoxicity, arthralgia/myalgia, and hypersensitivity were reported as more frequent and severe by patients treated with paclitaxel followed by cisplatin than patients treated with cyclophosphamide followed by cisplatin. Myelosuppression appeared to be less frequent and severe with paclitaxel as a three hour infusion followed by cisplatin compared with cyclophosphamide followed by cisplatin.

For the first line chemotherapy of metastatic breast cancer, neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were reported more frequently and with greater severity when paclitaxel (220 mg/m²) was administered as a 3-hour infusion 24 hours following doxorubicin (50 mg/m²) when compared to standard FAC therapy (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²). Nausea and vomiting appeared to be less frequent and severe with the paclitaxel (220 mg/m²) / doxorubicin (50 mg/m²) regimen as compared to the standard FAC regimen. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the paclitaxel/doxorubicin arm.

When paclitaxel was administered as a 3-hour infusion in combination with trastuzumab for the first line treatment of patients with metastatic breast cancer, the following events (regardless of relationship to paclitaxel or trastuzumab) were reported more frequently than with single agent paclitaxel: heart failure (8% vs 1%), infection (46% vs 27%), chills (42% vs 4%), fever (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhoea (45% vs 30%), hypertonia (11% vs 3%), epistaxis (18% vs 4%), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injury (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%), and injection site reaction (7% vs 1%). Some of these frequency differences may be due to the increased number and duration of treatments with paclitaxel/trastuzumab combination vs single agent paclitaxel. Severe events were reported at similar rates for paclitaxel/trastuzumab and single agent paclitaxel.

When doxorubicin was administered in combination with paclitaxel in metastatic breast cancer, cardiac contraction abnormalities (Congestive heart failure was observed in < 1% in both paclitaxel/doxorubicin and standard FAC arms. Administration of trastuzumab in combination with paclitaxel in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with paclitaxel single agent (New York Heart Association (NYHA) Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

AIDS-related Kaposi's sarcoma

Except for haematologic and hepatic undesirable effects (see below), the frequency and severity of undesirable effects are generally similar between KS patients and patients treated with paclitaxel monotherapy for other solid tumours, based on a clinical study including 107 patients.

Blood and the lymphatic system disorders: Bone marrow suppression was the major dose-limiting toxicity. Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (<0.5 x 10⁹/l) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia was present for>7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting

Neutropenic fever related to paclitaxel was reported in 14% of patients and in 1.3% of treatment cycles. There were 3 septic episodes (2.8%) during paclitaxel administration related to the medicinal product that proved fatal.

Thrombocytopenia was observed in 50% of patients, and was severe (<50 x 10⁹/l) in 9%. Only 14% experienced a drop in their platelet count <75 x 10⁹/l, at least once while on treatment. Bleeding episodes related to paclitaxel were reported in <3% of patients, but the haemorrhagic episodes were localised.

Anaemia (Hb <11 g/dl) was observed in 61% of patients and was severe (Hb <8 g/dl) in 10%. Red cell transfusions were required in 21% of patients.

Hepato-biliary disorders: Among patients (>50% on protease inhibitors) with normal baseline liver function, 28%, 43% and 44% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. For each of these parameters, the increases were severe in 1% of cases.

4.9 Overdose

There is no known antidote for paclitaxel overdose. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neuropathy, and mucositis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherpeutic group: Antineoplastic agent/taxanes

ATC code: L01C D01

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability inhibits the normal dynamic reorganisation of the microtubule network, which is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

In first-line treatment of ovarian cancer, the safety and efficacy of paclitaxel were evaluated in two major randomised controlled trials (compared with cyclophosphamide 750 mg/m² + cisplatin 75 mg/m² therapy).

In the Intergroup trial (BMS CA 139-209), over 650 patients with stage II_b-c, III or IV primary ovarian cancer had administered to them a maximum of 9 courses of treatment with paclitaxel (175 mg/m² over a 3-hour period) followed by cisplatin (75 mg/m²) or control treatment. In another major study (GOG 111/B-MS CA139-022), a maximum of 6 courses of treatment with paclitaxel were administered (135 mg/m², during a 24-hour infusion) combined with cisplatin (75 mg/m²) or control treatment; the trial involved over 400 patients with stage III or IV primary ovarian cancer with a> 1 cm residual tumour after staging laparotomy, or with distant metastases. While the two different posologies were not compared with each other directly, in both trials the patients on paclitaxel and cisplatin had a significantly higher response rate, later onset of progression of disease and longer survival time than the patients on standard therapy. Increased neurotoxicity, arthralgia/myalgia but reduced myelosuppression were observed in advanced ovarian cancer patients administered 3-hour infusion of paclitaxel/cisplatin as compared to patients who received cyclophosphamide/cisplatin.

In the adjuvant treatment of breast carcinoma, 3121 patients with node positive breast carcinoma were treated with adjuvant paclitaxel therapy or no chemotherapy following four courses of doxorubicin and cyclophosphamide (CALGB 9344, BMS CA 139-223). Median follow-up was 69 months. Overall, paclitaxel patients had a significant reduction of 18% in the risk of disease recurrence relative to patients receiving AC alone (p = 0.0014), and a significant reduction of 19% in the risk of death (p = 0.0044) relative to patients receiving AC alone. Retrospective analyses show benefit in all patient subsets. In patients with hormone receptor negative/ unknown tumors, reduction in risk of disease recurrence was 28% (95%CI: 0.59-0.86). In the patient subgroup with hormone receptor positive tumors, the risk reduction of disease recurrence was 9% (95%CI: 0.78-1.07). However, the design of the study did not investigate the effect of extended AC therapy beyond 4 cycles. It cannot be excluded on the basis of this study alone that the observed effects could be partly due to the difference in duration of chemotherapy between the two arms (AC 4 cycles; AC + paclitaxel 8 cycles). Therefore, adjuvant treatment with paclitaxel should be regarded as an alternative to extended AC therapy.

In a second large clinical study in adjuvant node positive breast cancer with a similar design, 3060 patients were randomized to receive or not four courses of paclitaxel at a higher dose of 225 mg/m² following four courses of AC (NSABP B-28, BMS CA139-270). At a median follow-up of 64 months, paclitaxel patients had a significant reduction of 17% in the risk of disease recurrence relative to patients who received AC alone (p = 0.006) ; paclitaxel treatment was associated with a reduction in the risk of death of 7% (95%CI: 0.78-1.12). All subset analyses favored the paclitaxel arm. In this study patients with hormone receptor positive tumor had a reduction in the risk of disease recurrence of 23% (95%CI: 0.6-0.92); in the patient subgroup with hormone receptor negative tumor the risk reduction of disease recurrence was 10% (95%CI: 0.7-1.11).

In the first-line treatment of metastatic breast cancer, the efficacy and safety of paclitaxel were evaluated in two pivotal, phase III, randomised, controlled open-label trials.

In the first study (BMS CA139-278), the combination of bolus doxorubicin (50 mg/m²) followed after 24 hours by paclitaxel (220 mg/m² by 3-hour infusion) (AT), was compared versus standard FAC regimen (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²), both administered every three weeks for eight courses. In this randomised study, 267 patients with metastatic breast cancer, who had either received no prior chemotherapy or only non-anthracycline chemotherapy in the adjuvant setting, were enrolled. Results showed a significant difference in time to progression for patients receiving AT compared to those receiving FAC (8.2 vs. 6.2 months; p= 0.029). The median survival was in favour of paclitaxel/doxorubicin vs. FAC (23.0 vs. 18.3 months; p= 0.004). In the AT and FAC treatment arm 44% and 48% respectively received follow-up chemotherapy which included taxanes in 7% and 50% respectively. The overall response rate was also significantly higher in the AT arm compared to the FAC arm (68% vs. 55%). Complete responses were seen in 19% of the paclitaxel/doxorubicin arm patients vs. 8% of the FAC arm patients. All efficacy results have been subsequently confirmed by a blinded independent review.

In the second study, the efficacy and safety of the paclitaxel and trastuzumab combination was evaluated in a planned subgroup analysis (metastatic breast cancer patients who formerly received adjuvant anthracyclines) of the study HO648g. The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been proven. The combination of trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) and paclitaxel (175 mg/m²) 3-hour infusion, every three weeks was compared to single-agent paclitaxel (175 mg/m²) 3-hour infusion, every three weeks in 188 patients with metastatic breast cancer overexpressing HER2 (2+ or 3+ as measured by immunohistochemistry), who had previously been treated with anthracyclines. Paclitaxel was administered every three weeks for at least six courses while trastuzumab was given weekly until disease progression. The study showed a significant benefit for the paclitaxel/trastuzumab combination in terms of time to progression (6.9 vs. 3.0 months), response rate (41% vs. 17%), and duration of response (10.5 vs. 4.5 months) when compared to paclitaxel alone. The most significant toxicity observed with the paclitaxel/trastuzumab combination was cardiac dysfunction (see section 4.8).

In the treatment of very advanced non-small cell lung cancer, the combination of 175 mg/m² of paclitaxel and 80 mg/m² of cisplatin (given after paclitaxel) has been studied in two phase III trials (367 patients on paclitaxel therapy). Both trials were randomised. In one of the trials the control group received cisplatin (100 mg/m²) and in another, 100 mg/m² of teniposide followed thereafter by 80 mg/m² of cisplatin (367 patients in the control group). The results of both trials were similar. There were no significant differences between the paclitaxel therapy and control therapy regarding mortality, primary end event (the median survival time in the paclitaxel groups were 8.1 and 9.5 months, and in the control groups 8.6 and 9.9 months). There were no significant differences in the median time of progression of the disease between the therapies either. The benefit was significant regarding clinical response. Studies on the quality of life indicate that the lack of appetite caused by combination treatment containing paclitaxel is smaller, but they also indicate an increased incidence of peripheral neuropathy (p<0.008) with combination treatment.

In the treatment of AIDS-related KS, the efficacy and safety of paclitaxel were investigated in a non-comparative study in patients with advanced KS, previously treated with systemic chemotherapy. The primary end-point was best tumour response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the core efficacy population. The overall success rate (complete/partial response) after 15 cycles of treatment was 57% (confidence interval (CI) 44 - 70%) in liposomal anthracycline-resistant patients. Over 50% of the responses were apparent after the first 3 cycles. In liposomal anthracycline-resistant patients, the response rates were comparable for patients who had never received a protease inhibitor (55.6%) and those who received one at least 2 months prior to treatment with paclitaxel (60.9%). The median time to progression in the core population was 468 days (95% CI 257-not estimable). Median survival could not be computed, but the lower 95% bound was 617 days in core patients.

5.2 Pharmacokinetic Properties

Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations.

The pharmacokinetics of paclitaxel were determined following 3- and 24-hour infusions at doses of 135 and 175 mg/m². The mean half-life was between 3.0 and 52.7 hours, and the mean non-compartmentally derived value for total body clearance was between 11.6 and 24.0 l/hr/m². The total body clearance appeared to decrease with higher plasma concentrations. The mean steady-state volume of distribution was between 198 and 688 l/m², indicating extensive extravascular distribution and/or tissue binding. Dose increases associated with the 3-hour infusion resulted in non-linear pharmacokinetics. When the dose increased by 30% from 135 mg/m² to 175 mg/m², the maximum plasma concentration (C_max) increased by 75% and the area under

Thyrogen 0.9 mg powder for solution for injection

THYROGEN 0.9 mg powder for solution for injection.

thyrotropin alfa

Read all of this leaflet carefully before you start using this medicine.

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


• If you have any further questions, ask your doctor or your pharmacist.


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

In this leaflet:

• 1. What Thyrogen is and what it is used for


• 2. Before you use Thyrogen


• 3. How to use Thyrogen


• 4. Possible Side Effects


• 5. How to store Thyrogen


• 6. Further Information

What Thyrogen Is And What It Is Used For

Thyrogen is a human thyroid stimulating hormone (TSH) manufactured using biotechnology processes.

Thyrogen is used to detect certain types of thyroid cancer in patients who have had their thyroid gland removed and who are taking thyroid hormones. One of the effects is that it stimulates any remaining thyroid tissue to take up iodine which is important for radioiodine imaging. It also stimulates the production of thyroglobulin and thyroid hormones if there is any thyroid tissue left.

These hormones can be measured in your blood.

Thyrogen is also used with radioiodine treatment to eliminate (ablate) the thyroid tissue left over after surgical removal of the thyroid gland (remnant) in patients who do not have secondaries (metastases) and who are taking thyroid hormone.

Before You Use Thyrogen

Do not use Thyrogen

Tell your doctor:

• if have ever had an allergic reaction (for example, rash or itchiness) to bovine or human thyroid stimulating hormone (TSH).


• if you are allergic to any of the other ingredients before you take this medicine (these are listed in Section 6; see also at the end of Section 2).


• if you are pregnant.

Take special care with Thyrogen

Thyrogen should never be injected into a vein.

Tell your doctor if you have:

• kidney disease that require dialysis and he/she will decide how much Thyrogen to give to you as you may have more chance of experiencing headache and nausea.


• reduced kidney function and he/she will decide how much radioiodine to give you.


• reduced liver function; you should still be able to receive Thyrogen.

Elderly patients

No special precautions for elderly patients are necessary. However if your thyroid gland has not been removed completely and you are also suffering from heart disease, your doctor will help you decide if Thyrogen should be given to you.

Effect on tumour growth

In patients with thyroid cancer, tumour growth has been reported during withdrawal of thyroid hormones for diagnostic procedures. This was thought to be related to the elevated thyroid stimulating hormone (TSH) levels over a longer period. It is possible that Thyrogen may also cause tumour growth. In clinical trials this was not seen.

Due to elevation of TSH levels after Thyrogen, patients with secondary cancer growths (metastases) can experience local swelling or bleeding at the site of these metastases which may become bigger. If the metastases are present in narrow spaces e.g. intracerebral (in the brain) or in the spinal cord, patients could experience rapid symptoms such as partial paralysis affecting one side of the body (hemiparesis), breathing problems or loss of vision.

Your doctor will decide if you belong to a specific group of patients for which pre-treatment with corticosteroids is to be considered (for example, if you have secondary cancer growths in your brain or spinal cord ). Please talk to your doctor about this if you have concerns.

Using other medicines

There are no known drug interactions with Thyrogen and the thyroid hormones you may be taking.

Please tell you doctor if you are taking or have recently taken any other medicines including medicines obtained without prescription.

Your doctor will determine the exact activity of radioiodine to use for radioiodine imaging, taking into consideration the fact that you continue to take thyroid hormones.

Pregnancy and breast-feeding

Ask your doctor for advice before taking any medicine.

Do not take Thyrogen if you are pregnant. Please consult your doctor if you are pregnant or think you may be pregnant.

Thyrogen should not be given to breastfeeding women. Breast-feeding should only be resumed following advice from your doctor.

Driving and using machines

Some patients may feel dizzy or have headaches after administration of Thyrogen which may affect the ability to drive and use machines.

Important information about some of the ingredients of Thyrogen

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially ‘sodium- free’.

How To Use Thyrogen

Your doctor, nurse or pharmacist will prepare the injection for you.

Your treatment should be supervised by a doctor who has expertise in thyroid cancer. Thyrogen powder must be dissolved in water for injection. Only one vial of Thyrogen is required per injection. The injection must be given intra-muscularly. Thyrogen must not be mixed with other medicines in the same injection

Use in children

Your child’s doctor will help you decide if Thyrogen should be given to your child.

Dosage:

The recommended dose of Thyrogen is two doses administered 24 hours apart. Your doctor or nurse will inject 1.0 ml of the Thyrogen solution.

Thyrogen should only be administered into the buttock muscle. Thyrogen solution should never be injected into a vein.

If you have

• reduced liver function you should still be able to receive Thyrogen.


• kidney disease that require dialysis and your doctor will decide how much Thyrogen to give to you. You may have more chance of experiencing headache and nausea after receiving Thyrogen.


• reduced kidney function your doctor will decide how much radioiodine to give you.

When you undergo radioiodine imaging or elimination (ablation), your doctor will give you radioiodine 24 hours after your final Thyrogen injection.

Diagnostic scanning should be performed 48 to 72 hours after the radioiodine administration (72 to 96 hours after the final injection of Thyrogen).

Post-treatment scanning may be delayed a few days to allow background radioactivity to decline.

For thyroglobulin (Tg) testing, your doctor or nurse will take a serum sample 72 hours after the last injection of Thyrogen.

If you are given more Thyrogen than you should receive

Patients who accidentally received too much Thyrogen have reported nausea, weakness, dizziness, headache, vomiting and hot flashes.

If you have any further questions on the use of this product, ask your doctor.

Possible Side Effects

Like all medicines, Thyrogen can cause side effects although not everybody gets them.

The following effects have been reported with Thyrogen:

Very common (affects more than 1 user in 10):

• nausea

Common (affects 1 to 10 users in 100):

• vomiting


• fatigue


• dizziness


• headache,


• diarrhoea,


• weakness,


• prickling or tingling sensation (paraesthesia).

Uncommon (affects 1 to 10 users in 1,000):

• feeling hot


• hives (urticaria)


• rash


• flu symptoms


• fever


• chills


• back pain

Frequency not known

(frequency cannot be estimated from the available data)

• swelling of the tumour


• pain (including pain at the site of metastases (secondary cancer growths))


• tremor


• palpitations


• flushing


• shortness of breath


• itching (pruritus)


• excessive sweating


• muscle or joint pain


• injection site reactions (including: redness, discomfort, itching, local pain or stinging, and an itchy rash)


• low TSH


• hypersensitivity (allergic reactions), these reactions include hives (urticaria), itching, flushing, difficulty in breathing and rash.

Very rare cases of hyperthyroidism (increased activity of the thyroid gland) or atrial fibrillation have been reported when Thyrogen was administered to patients who had not undergone total or partial removal of the thyroid gland.

If any of the side effects gets serious, or if any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Thyrogen

Keep out of the reach and sight of children.

Do not use after the expiry date which is stated on the label after "EXP". The expiry date refers to the last day of that month.

Store in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Thyrogen contains

The active substance in Thyrogen is thyrotropin alfa.

Each vial contains 0.9 mg/ml of thyrotropin alfa when reconstituted with 1.2 ml water for injection. Only 1 ml should be withdrawn equal to 0.9 mg of thyrotropin alfa.

The other ingredients are:

• mannitol


• sodium phosphate monobasic, monohydrate


• sodium phosphate dibasic, heptahydrate


• sodium chloride

(see at the end of Section 2 "Important information about some of the ingredients of Thyrogen")

What Thyrogen looks like and contents of the pack

Powder for solution for injection. White to off-white lyophilised powder.

Pack sizes: one or two vials of Thyrogen per carton.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing authorisation holder:

Genzyme Europe B.V.

Gooimeer 10

1411 DD Naarden

The Netherlands

Manufacturing authorisation holder:

Genzyme Ltd.

37 Hollands Road

Haverhill

Suffolk

CB9 8PU

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom/Ireland

Genzyme Therapeutics

United Kingdom

Tel: +44 1865 405200

This leaflet was last approved in 01/2010

Detailed information on this medicine is available on the European Medicines Agency (EMEA) website: http://www.emea.europa.eu. There are also links to other websites about rare diseases and treatments.

Avosil Topical

Generic Name: salicylic acid (Topical route)

sal-i-SIL-ik AS-id

Commonly used brand name(s)

In the U.S.

• Akurza


• Aliclen


• Avosil


• Betasal


• Compound W


• Corn Removing


• Dermarest Psoriasis


• DHS Sal


• Drytex


• Duofilm


• Duoplant


• Durasal


• Freezone


• Fung-O


• Gets-It Corn/Callus Remover


• Gordofilm


• Hydrisalic


• Ionil


• Ionil Plus


• Keralyt


• Keralyt Scalp


• Lupicare


• Mediplast


• Mg217 Sal-Acid


• Mosco Corn & Callus Remover


• Neutrogena


• Occlusal-HP


• Off-Ezy


• Oxy Balance


• P & S


• Palmer's Skin Success Acne Cleanser


• Propa pH


• Salac


• Sal-Acid Plaster


• Salactic Film


• Salex


• Salitop


• Salkera


• Sal-Plant Gel


• Salvax


• Seba-Clear


• Stri-Dex


• Thera-Sal


• Therasoft Anti-Acne


• Tinamed


• Ti-Seb


• Virasal


• Wart-Off Maximum Strength


• Zapzyt

In Canada

• Acnex


• Acnomel Acne Mask


• Clear Away Wart Removal System


• Compound W One-Step Wart Remover


• Compound W Plus


• Dr. Scholl's Clear Away One Step Plantar Wart Remover


• Dr. Scholl's Cushlin Ultra Slim Callus Removers


• Dr. Scholl's Cushlin Ultra Slim Corn Removers


• Duoforte 27


• Freezone - One Step Callus Remover Pad


• Freezone - One Step Corn Remover Pad

Available Dosage Forms:

• Soap


• Lotion


• Liquid


• Foam


• Ointment


• Gel/Jelly


• Solution


• Cream


• Pad


• Paste


• Shampoo


• Dressing


• Stick

Therapeutic Class: Antiacne

Pharmacologic Class: NSAID

Chemical Class: Salicylate, Non-Aspirin

Uses For Avosil

Salicylic acid is used to treat many skin disorders, such as acne, dandruff, psoriasis, seborrheic dermatitis of the skin and scalp, calluses, corns, common warts, and plantar warts, depending on the dosage form and strength of the preparation.

Some of these preparations are available only with your doctor's prescription.

Before Using Avosil

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

Young children may be at increased risk of unwanted effects because of increased absorption of salicylic acid through the skin. Also, young children may be more likely to get skin irritation from salicylic acid. Salicylic acid should not be applied to large areas of the body, used for long periods of time, or used under occlusive dressing (air-tight covering, such as kitchen plastic wrap) in infants and children. Salicylic acid should not be used in children younger than 2 years of age.

Geriatric

Elderly people are more likely to have age-related blood vessel disease. This may increase the chance of problems during treatment with this medicine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Argatroban


• Bivalirudin


• Cilostazol


• Citalopram


• Clovoxamine


• Dabigatran Etexilate


• Dipyridamole


• Escitalopram


• Femoxetine


• Flesinoxan


• Fluoxetine


• Fluvoxamine


• Fondaparinux


• Heparin


• Lepirudin


• Nefazodone


• Paroxetine


• Protein C


• Rivaroxaban


• Sertraline


• Sibutramine


• Ticlopidine


• Tirofiban


• Vilazodone


• Zimeldine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol


• Anisindione


• Ardeparin


• Azilsartan Medoxomil


• Azosemide


• Bemetizide


• Bendroflumethiazide


• Benzthiazide


• Bumetanide


• Buthiazide


• Candesartan Cilexetil


• Certoparin


• Chlorothiazide


• Chlorthalidone


• Clopamide


• Cyclopenthiazide


• Dalteparin


• Danaparoid


• Dicumarol


• Enoxaparin


• Eprosartan


• Ethacrynic Acid


• Furosemide


• Hydrochlorothiazide


• Hydroflumethiazide


• Indapamide


• Irbesartan


• Losartan


• Methyclothiazide


• Metolazone


• Nadroparin


• Olmesartan Medoxomil


• Parnaparin


• Phenindione


• Phenprocoumon


• Piretanide


• Polythiazide


• Probenecid


• Reviparin


• Tamarind


• Tasosartan


• Telmisartan


• Tinzaparin


• Torsemide


• Trichlormethiazide


• Valsartan


• Warfarin


• Xipamide

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.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood vessel disease

• Diabetes mellitus (sugar diabetes)—Use of this medicine may cause severe redness or ulceration, especially on the hands or feet

• Inflammation, irritation, or infection of the skin—Use of this medicine may cause severe irritation if applied to inflamed, irritated, or infected area of the skin

• Influenza (flu) or


• Varicella (chicken pox)—This medicine should not be used in children and teenagers with the flu or chicken pox. There is a risk of Reye's syndrome.

• Kidney disease or


• Liver disease—Using this medicine for a long time over large areas could result in unwanted effects

Proper Use of salicylic acid

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

It is very important that you use this medicine only as directed. Do not use more of it, do not use it more often, and do not use it for a longer time than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of absorption through the skin and the chance of salicylic acid poisoning.

If your doctor has ordered an occlusive dressing (airtight covering, such as kitchen plastic wrap) to be applied over this medicine, make sure you know how to apply it. Since an occlusive dressing will increase the amount of medicine absorbed through your skin and the possibility of salicylic acid poisoning, use it only as directed. If you have any questions about this, check with your doctor.

Keep this medicine away from the eyes and other mucous membranes, such as the mouth and inside of the nose. If you should accidentally get some in your eyes or on other mucous membranes, immediately flush them with water for 15 minutes.

To use the cream, lotion, or ointment form of salicylic acid:

• Apply enough medicine to cover the affected area, and rub in gently.

To use the gel form of salicylic acid:

• Before using salicylic acid gel, apply wet packs to the affected areas for at least 5 minutes. If you have any questions about this, check with your health care professional.


• Apply enough gel to cover the affected areas, and rub in gently.

To use the pad form of salicylic acid:

• Wipe the pad over the affected areas.


• Do not rinse off medicine after treatment.

To use the plaster form of salicylic acid for warts, corns, or calluses:

• This medicine comes with patient instructions. Read them carefully before using.


• Do not use this medicine on irritated skin or on any area that is infected or reddened. Also, do not use this medicine if you are a diabetic or if you have poor blood circulation.


• Do not use this medicine on warts with hair growing from them or on warts on the face, in or on the genital (sex) organs, or inside the nose or mouth. Also do not use on moles or birthmarks. To do so may cause severe irritation.


• Wash the area to be treated and dry thoroughly. Warts may be soaked in warm water for 5 minutes before drying.


• Cut the plaster to fit the wart, corn, or callus and apply.


• For corns and calluses:
  
  • Repeat every 48 hours as needed for up to 14 days, or as directed by your doctor, until the corn or callus is removed.
  
  
  • Corns or calluses may be soaked in warm water for 5 minutes to help in their removal.
  
  


• For warts:
  
  • Depending on the product, either:
    
    • Apply plaster and repeat every 48 hours as needed, or
      
      • Apply plaster at bedtime, leave in place for at least 8 hours, remove plaster in the morning, and repeat every 24 hours as needed.
      
      
    
    
  
  
  • Repeat for up to 12 weeks as needed, or as directed by your doctor, until wart is removed.
  
  


• If discomfort gets worse during treatment or continues after treatment, or if the wart spreads, check with your doctor.

To use the shampoo form of salicylic acid:

• Before applying this medicine, wet the hair and scalp with lukewarm water. Apply enough medicine to work up a lather and rub well into the scalp for 2 or 3 minutes, then rinse. Apply the medicine again and rinse thoroughly.

To use the soap form of salicylic acid:

• Work up a lather with the soap, using hot water, and scrub the entire affected area with a washcloth or facial sponge or mitt.


• If you are to use this soap in a foot bath, work up rich suds in hot water and soak the feet for 10 to 15 minutes. Then pat dry without rinsing.

To use the topical solution form of salicylic acid for acne:

• Wet a cotton ball or pad with the topical solution and wipe the affected areas.


• Do not rinse off medicine after treatment.

To use the topical solution form of salicylic acid for warts, corns, or calluses:

• This medicine comes with patient instructions. Read them carefully before using.


• This medicine is flammable. Do not use it near heat or open flame or while smoking.


• Do not use this medicine on irritated skin or on any area that is infected or reddened. Also, do not use this medicine if you are a diabetic or if you have poor blood circulation.


• Do not use this medicine on warts with hair growing from them or on warts on the face, in or on the genital (sex) organs, or inside the nose or mouth. Also do not use on moles or birthmarks. To do so may cause severe irritation.


• Avoid breathing in the vapors from the medicine.


• Wash the area to be treated and dry thoroughly. Warts may be soaked in warm water for 5 minutes before drying.


• Apply the medicine one drop at a time to completely cover each wart, corn, or callus. Let dry.


• For warts—Repeat one or two times a day as needed for up to 12 weeks, or as directed by your doctor, until wart is removed.


• For corns and calluses—Repeat one or two times a day as needed for up to 14 days, or as directed by your doctor, until the corn or callus is removed.


• Corns and calluses may be soaked in warm water for 5 minutes to help in their removal.


• If discomfort gets worse during treatment or continues after treatment, or if the wart spreads, check with your doctor.

Unless your hands are being treated, wash them immediately after applying this medicine to remove any medicine that may be on them.

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 cream dosage form:
  
  • For corns and calluses:
    
    • Adults and children—Use the 2 to 10% cream as needed. Use the 25 to 60% cream one time every three to five days.
    
    
  
  


• For gel dosage form:
  
  • For acne:
    
    • Adults and children—Use the 0.5 to 5% gel one time a day.
    
    
  
  
  • For psoriasis:
    
    • Adults and children—Use the 5% gel one time a day.
    
    
  
  
  • For common warts:
    
    • Adults and children—Use the 5 to 26% gel one time a day.
    
    
  
  


• For lotion dosage form:
  
  • For acne:
    
    • Adults and children—Use the 1 to 2% lotion one to three times a day.
    
    
  
  
  • For dandruff and antiseborrhic dermatitis of the scalp:
    
    • Adults and children—Use the 1.8 to 2% lotion on the scalp one or two times a day.
    
    
  
  


• For ointment dosage form:
  
  • For acne:
    
    • Adults and children—Use the 3 to 6% ointment as needed.
    
    
  
  
  • For psoriasis and seborrheic dermatitis:
    
    • Adults and children—Use the 3 to 10% ointment as needed.
    
    
  
  
  • For common warts:
    
    • Adults and children—Use the 3 to 10% ointment as needed. Use the 25 to 60% ointment one time every three to five days.
    
    
  
  


• For pads dosage form:
  
  • For acne:
    
    • Adults and children—Use one to three times a day.
    
    
  
  


• For plaster dosage form:
  
  • For corns, calluses, common warts, or plantar warts:
    
    • Adults and children—Use one time a day or one time every other day.
    
    
  
  


• For shampoo dosage form:
  
  • For dandruff or seborrheic dermatitis of the scalp:
    
    • Adults and children—Use on the scalp one or two times a week.
    
    
  
  


• For soap dosage form:
  
  • For acne:
    
    • Adults and children—Use as needed.
    
    
  
  


• For topical solution dosage form:
  
  • For acne:
    
    • Adults and children—Use the 0.5 to 2% topical solution one to three times a day.
    
    
  
  
  • For common warts and plantar warts:
    
    • Adults and children—Use the 5 to 27% topical solution one or two times a day.
    
    
  
  
  • For corns and calluses:
    
    • Adults and children—Use the 12 to 27% topical solution one or two times a day.
    
    
  
  

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 Avosil

When using salicylic acid, do not use any of the following preparations on the same affected area as this medicine, unless otherwise directed by your doctor:

• Abrasive soaps or cleansers


• Alcohol-containing preparations


• Any other topical acne preparation or preparation containing a peeling agent (for example, benzoyl peroxide, resorcinol, sulfur, or tretinoin [vitamin A acid])


• Cosmetics or soaps that dry the skin


• Medicated cosmetics


• Other topical medicine for the skin

To use any of the above preparations on the same affected area as salicylic acid may cause severe irritation of the skin.

Check with your doctor right away if you have nausea, vomiting, dizziness, loss of hearing, tinnitus, lethargy hyperpnea, diarrhea, and psychic disturbances. These could be symptoms of a serious condition called salicylate toxicity, especially in children under 12 years of age and patients with kidney or liver problems.

Avosil 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 or rare

• Skin irritation not present before use of this medicine (moderate or severe)

Frequency not known

• Dryness and peeling of skin


• flushing


• redness of skin


• unusually warm skin

Symptoms of salicylic acid poisoning

• Confusion


• diarrhea


• dizziness


• fast or deep breathing


• headache (severe or continuing)


• hearing loss


• lightheadedness


• nausea


• rapid breathing


• ringing or buzzing in ears (continuing)


• severe drowsiness


• stomach pain


• vomiting

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:

More common

• Skin irritation not present before use of this medicine (mild)


• stinging

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: Avosil 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.

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More Avosil Topical resources

• Avosil Topical Side Effects (in more detail)
• Avosil Topical Use in Pregnancy & Breastfeeding
• Avosil Topical Drug Interactions
• Avosil Topical Support Group
• 1 Review for Avosil Topical - Add your own review/rating

Compare Avosil Topical with other medications

• Acne
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