Cardura XL

doxazosin mesylate

Dosage Form: tablet, multilayer, extended release
FULL PRESCRIBING INFORMATION

Indications and Usage for Cardura XL

CARDURA® XL (doxazosin mesylate extended release tablets) is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Cardura XL is not indicated for the treatment of hypertension.

Cardura XL Dosage and Administration

General Dosing Information

The initial dose of Cardura XL, 4 mg given once daily, should be administered with breakfast. Depending on the patient's symptomatic response and tolerability, the dose may be increased to 8 mg, the maximum recommended dose. The recommended titration interval is 3–4 weeks. If Cardura XL administration is discontinued for several days, therapy should be restarted using the 4 mg once daily dose. Tablets should be swallowed whole, and must not be chewed, divided, cut, or crushed.

Patients Switching from CARDURA to Cardura XL

If switching from CARDURA immediate-release (IR) to Cardura XL, therapy should be initiated with the lowest dose (4 mg once daily). Prior to starting therapy with Cardura XL, the final evening dose of CARDURA should not be taken.

Concomitant Administration with PDE-5 Inhibitors

Concomitant administration of Cardura XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking Cardura XL.

Dosage Forms and Strengths

White, round, film-coated tablets containing 4 mg and 8 mg doxazosin mesylate.

Contraindications

Cardura XL is contraindicated in patients with a known hypersensitivity to doxazosin, other quinazolines (e.g., prazosin, terazosin), or any of the inert ingredients. Allergic reactions to doxazosin and other quinazolines have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see Adverse Reactions (6.2)].

Warnings and Precautions

Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of Cardura XL. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. Care should be taken when Cardura XL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

Cataract Surgery

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit from stopping alpha1 blocker therapy prior to cataract surgery.

Gastrointestinal Disorders

As with any other non-deformable material, caution should be used when administering Cardura XL to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable extended release formulation. Markedly increased GI retention times, as may occur in patients with chronic constipation, can increase systemic exposure to doxazosin and thereby potentially increase adverse reactions.

Prostate Cancer

Carcinoma of the prostate causes many of the same symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with Cardura XL.

PDE-5 Inhibitors

Concomitant administration of Cardura XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Pharmacodynamic interactions between Cardura XL and antihypertensive medications or other vasodilating agents have not been determined.

Patients with Hepatic Impairment

Cardura XL is not recommended for patients with severe hepatic impairment and should be administered with caution to patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Patients with Coronary Insufficiency

Patients with congestive heart failure, angina pectoris, or acute myocardial infarction within the last 6 months were excluded from the Phase 3 studies. If symptoms of angina pectoris should newly appear or worsen, Cardura XL should be discontinued.

CYP 3A4 Inhibitors

Caution should be exercised when concomitantly administering Cardura XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole.

Adverse Reactions

Clinical Trials Experience

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

The incidence of adverse reactions was derived from two controlled efficacy and safety trials involving 1473 BPH patients. In Study 1, Cardura XL (n=317) was compared to doxazosin IR tablets (n=322) and to placebo (n=156). In Study 2, Cardura XL (n=350) was compared just to doxazosin IR tablets (n=330). In both of these studies, Cardura XL was initiated at a dose of 4 mg, which could be increased by the investigator to 8 mg after seven weeks if an adequate response was not seen [see Clinical Studies (14.1)]. Similarly, doxazosin IR was begun at a dose of 1 mg, which was increased in all patients to 2 mg after 1 week, followed by the option to increase to 4 mg after 4 weeks, and 8 mg after 7 weeks.

The most commonly reported adverse reactions leading to discontinuation in the Cardura XL group were: dizziness, dyspnea, asthenia, headache, hypotension, postural hypotension, and somnolence. The rates of discontinuation for adverse reactions were 6%, 7% and 3% in the Cardura XL, doxazosin IR, and placebo groups, respectively.

Table 1 lists the incidence rates of adverse reactions derived from all reported adverse events in the two controlled studies (Studies 1 and 2) combined, at a rate greater than placebo and in 1% or more of patients treated with Cardura XL.

TABLE 1 Adverse Reactions, Derived from All Adverse Events Exceeding Placebo Rate and Occurring in ≥1% of BPH Patients Treated with Cardura XL

Body System	Cardura XL (N = 666)	Doxazosin IR (N = 651)	Placebo (N = 156)
BODY AS A WHOLE
Abdominal Pain	1.8%	2.3%	0.6%
Asthenia	3.9%	6.9%	1.3%
Headache	6.0%	5.1%	4.5%
CARDIOVASCULAR
Hypotension	1.7%	1.8%	0.0%
Postural Hypotension	1.2%	2.2%	0.6%
DIGESTIVE
Dyspepsia	1.4%	1.2%	0.0%
Nausea	1.2%	2.3%	0.6%
MUSCULOSKELETAL
Myalgia	1.4%	0.5%	0.0%
NERVOUS
Dizziness	5.3%	9.1%	1.9%
Somnolence	1.5%	1.2%	0.0%
Vertigo	1.5%	4.1%	0.6%
RESPIRATORY
Dyspnea	1.2%	1.2%	0.0%
Respiratory Tract Infection	4.8%	4.5%	1.9%
UROGENITAL
Urinary Tract Infection	1.4%	0.8%	0.6%

Additional adverse events reported with Cardura XL, reported by less than 1% of patients, and those of clinical interest include: Cardiovascular System: angina pectoris, syncope, tachycardia, chest pain, palpitations; Digestive System: diarrhea; Musculoskeletal System: arthralgia; Nervous System: libido decreased; Urogenital System: impotence, dysuria.

In general, the adverse events reported in the open-label safety extension, in approximately 295 BPH patients treated for up to 37 weeks, were similar in type and frequency to the events described above in the controlled trials.

Postmarketing Experience

The following adverse events have been identified during post-approval use of doxazosin IR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Autonomic Nervous System: priapism; Cardiovascular System: cerebrovascular accidents, dizziness postural, myocardial infarction; Central and Peripheral Nervous System: hypoesthesia, paresthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: fatigue, hot flushes, malaise; Heart Rate/Rhythm: bradycardia, cardiac arrhythmias; Hematopoietic: leukopenia, purpura, thrombocytopenia; Liver/Biliary System: abnormal liver function tests, hepatitis, hepatitis cholestatic, jaundice; Musculoskeletal System: muscle cramps, muscle weakness; Psychiatric: agitation, anorexia, nervousness; Respiratory System: bronchospasm aggravated; Skin Disorders: alopecia, urticaria, skin rash, pruritus; Special Senses: blurred vision, Intraoperative Floppy Iris Syndrome [see Warnings and Precautions (5.2)]; Urinary System: hematuria, micturition disorder, micturition frequency, nocturia, polyuria.

There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain.

Drug Interactions

CYP 3A4 Inhibitors

No in vivo drug interaction studies were conducted with Cardura XL.

In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering Cardura XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole [see Clinical Pharmacology (12.3)].

Antihypertensive Medications

Pharmacodynamic interactions between Cardura XL and antihypertensive medications or other vasodilating agents have not been determined.

PDE-5 Inhibitors

Concomitant administration of Cardura XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension [see Dosage and Administration (2.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C: Cardura XL is not indicated for use in women. Doxazosin base was found to cross the placenta following oral administration to pregnant rats, resulting in fetal exposure. There was no evidence of teratogenicity or embryotoxicity in rat or rabbit fetuses at exposures 32- and 13- fold greater than the AUC values for doxazosin base in men given the maximum recommended human dose (MHRD) of 8 mg Cardura XL. Maternal rat and rabbit doses were 20 mg/kg/day or 41 mg/kg/day doxazosin base, respectively, administered during major organ development. Embryolethality was observed in rabbits at a dose of 100 mg/kg/day of doxazosin mesylate when administered during major organ development. There are no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects: In pre- and postnatal development studies in rats, postnatal development was delayed, as evidenced by body weight gain suppression and a slight delay in the appearance of developmental anatomical landmarks and reflexes at a doxazosin base exposure of 26-fold above the human exposure (AUC) at the MHRD of 8 mg Cardura XL.

Nursing Mothers

Doxazosin base was secreted into the milk in lactating rats at concentrations approximately 20-fold above the exposure found in the maternal plasma following an oral dose of 1 mg/kg. It is not known if doxazosin is excreted in human breast milk. Use of Cardura XL in nursing mothers is not recommended.

Pediatric Use

The safety and effectiveness of Cardura XL in pediatric patients have not been established.

Geriatric Use

The incidence of hypotension with Cardura XL use appears to be age related and more prevalent in patients 70 years or older. At steady state, increases of 27% in maximum plasma concentrations (Cmax) and 34% in the area under the concentration-time curve (AUC) were seen in the elderly (>65 years old) compared to the young [see Clinical Pharmacology (12.3)].

Of the 666 patients with BPH who received Cardura XL in the two controlled clinical efficacy and safety studies, 325 patients (49%) were 65 years of age or older. One hundred thirty-six patients treated with Cardura XL (20%) were >70 years of age.

In these two studies, the cumulative incidence of hypotension appeared to be age related. The reason for an increased incidence of hypotension in patients older than 70 years of age may be related to a modest increase in systemic exposure to doxazosin [see Clinical Pharmacology (12.3)], to an increased propensity to orthostasis in the elderly, or to an enhanced sensitivity to vasodilatory agents in the elderly. The incidence of hypotension reported as an adverse reaction was higher in patients 70 years of age and older (4/136; 2.9%) as compared to patients < 70 years of age (7/530; 1.3%).

Hepatic Impairment

Since there is no clinical experience in patients with severe hepatic impairment, use in these patients is not recommended. Cardura XL should be administered with caution to patients with mild or moderate hepatic impairment [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

Overdosage

There is no experience with Cardura XL overdosage. Overdosage experience with the doxazosin IR is limited. Two adolescents who each intentionally ingested 40 mg doxazosin IR with diclofenac or paracetamol were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidentally ingested 4 mg doxazosin IR was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin IR and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin IR (blood level 0.9 µg/mL; normal values in hypertensives=0.02 µg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg doxazosin IR, alcohol, and Dalmane® (flurazepam) developed hypotension which responded to fluid therapy.

The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid, keeping the patient in the supine position, and in certain circumstances, the administration of vasopressors. As doxazosin is highly protein bound, dialysis would not be indicated.

Cardura XL Description

Cardura XL contains doxazosin mesylate which is a quinazoline compound with the chemical name 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5 • CH4O3S and the molecular weight is 547.6. It has the following structure:

Cardura XL is an extended release tablet for oral use and is designed to deliver 4 or 8 mg of doxazosin as the free base. Each 4 and 8 mg tablet contains 5.1 and 10.2 mg doxazosin mesylate (includes a 5% overage) to provide 4 and 8 mg doxazosin as a free base, respectively. The inactive ingredients for Cardura XL are: polyethylene oxide, sodium chloride, hypromellose, red ferric oxide, titanium dioxide, magnesium stearate, cellulose acetate, Macrogol®, pharmaceutical glaze, and black iron oxide.

Cardura XL System Components and Performance

Cardura XL is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water, but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet.

Cardura XL utilizes GITS (Gastrointestinal Therapeutic System) which is designed to provide a controlled rate of delivery of doxazosin into the gastrointestinal lumen which is independent of pH or gastrointestinal (GI) motility. The function of Cardura XL depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell.

Cardura XL - Clinical Pharmacology

Mechanism of Action

The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule, and bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve the BPH symptoms and improve urine flow. Doxazosin mesylate is a selective inhibitor of the alpha1-subtype of alpha adrenergic receptors. In the human prostate, doxazosin mesylate antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1A adrenoceptor.

Pharmacodynamics

Administration of Cardura XL to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate [see Clinical Studies (14.1)].

Pharmacokinetics

The pharmacokinetics of Cardura XL is different from that of doxazosin IR. Cardura XL provides a controlled release of doxazosin over a 24-hour period.

Absorption: Pharmacokinetic parameters describing absorption following 4 and 8 mg Cardura XL daily doses are reported in Table 2 below. The relative bioavailability of Cardura XL compared with doxazosin IR was 54% at the 4 mg dose and 59% for the 8 mg dose.

TABLE 2 Mean (±SD) Plasma Concentration of Doxazosin at Steady State in Healthy Volunteers: Pharmacokinetic Parameters

Parameter	Cardura XL (4 mg)	Cardura XL (8 mg)
Cmax (ng/mL)	10.1 ± 5.6	25.8 ± 12.1
AUC(0 – ∞)	183 ± 85.5	472 ± 170.8
Tmax (h)	8 ± 3.7	9 ± 4.7

Food Effect: As illustrated in Figure 1, the plasma Cmax and AUC were approximately 32% and 18% higher, respectively, after Cardura XL was administered in the fed state compared with the fasted state. In order to provide the most consistent exposure, Cardura XL should be administered with breakfast [see Dosage and Administration (2.1)].

GI Retention Time Effect: Markedly reduced GI retention times (e.g., short bowel syndrome) may influence the pharmacokinetics of Cardura XL and possibly result in lower plasma concentrations. Conversely, markedly prolonged GI retention times (e.g., chronic constipation) can increase systemic exposure to doxazosin and potentially result in increased adverse reactions [see Warnings and Precautions (5.3)].

Distribution: At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

Metabolism: Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C19 metabolic pathways also exist to a lesser extent. No in vivo drug interaction studies have been performed with Cardura XL. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites has not been characterized [see Drug Interactions (7)].

Excretion: In a study of two subjects administered radiolabeled doxazosin IR 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average, only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. The apparent elimination half-life of Cardura XL is 15–19 hours.

Drug-Drug Interactions

No in vivo drug-drug interaction studies have been performed to assess the effect of concomitant medications on the pharmacokinetics of Cardura XL or to assess the effect of Cardura XL on the pharmacokinetics of other drugs. In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering Cardura XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole

In one placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin IR on day 1 of a four day regimen of cimetidine (400 mg twice daily) resulted in a 10% increase in the mean AUC of doxazosin, a 6% increase in mean Cmax of doxazosin, and no significant change in mean half-life of doxazosin. Based upon the differences in dose and formulation, the applicability of these results to Cardura XL is unknown. Otherwise, the interaction potential with other inhibitors or substrates of CYP enzymes has not been determined. Pharmacodynamic interactions between Cardura XL and anti-hypertensive medications or other vasodilating agents have also not been determined. Finally, drugs which reduce gastrointestinal motility leading to markedly prolonged GI retention times (e.g., anticholinergic agents) may increase systemic exposure to doxazosin.

Use in Specific Populations

Geriatric: In a study to assess the effect of age on the pharmacokinetics of Cardura XL, increases of 27% in plasma Cmax and 34% in the plasma AUC were seen at steady state in the elderly (>65 years old) compared to the young [see Use in Specific Populations (8.5)].

Hepatic Impairment: Administration of a single 2 mg dose of doxazosin IR to patients with mild hepatic impairment (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin compared to patients without hepatic impairment. No studies have been performed to assess the effect of hepatic impairment on the pharmacokinetics of Cardura XL. Use in patients with severe hepatic impairment is not recommended. Cardura XL should be administered with caution to patients with evidence of mild or moderately impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis: Doxazosin mesylate was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 40 mg/kg/day or 120 mg/kg/day, respectively. Systemic drug exposures, as measured by AUC, were approximately 34-fold in rats and 16-fold in mice above the exposures at the maximum human recommended dose (MHRD) of 8 mg Cardura XL.

Doxazosin base was not mutagenic in the in vitro bacterial Ames assays, the chromosomal aberration assay in human lymphocytes, or the mouse lymphoma assay. Doxazosin was not clastogenic in the in vivo mouse micronucleus assay. Doxazosin mesylate has not been evaluated for genotoxicity.

Fertility in Males: Studies in rats after oral administration of doxazosin base showed reduced fertility in males, which was reversible after two weeks of treatment termination at doxazosin base exposure of 13-fold above the human exposure (AUC) at the MHRD of 8 mg Cardura XL. There have been no reports of any effects of doxazosin on male fertility in humans.

Cardiac Toxicity in Animals

Studies in Sprague-Dawley rats after 6, 12, and 18 months, and in CD-1 mice after 18 months of dietary administration, showed an increased incidence of myocardial necrosis or fibrosis at doxazosin base exposure of 26-fold above the human exposure (AUC) at the MHRD of 8 mg Cardura XL. No cardiotoxicity was observed in dogs or Wistar rats after 12 months of oral dosing at doxazosin base exposures of 65- and 85-fold, respectively, above the human exposure (Cmax) at the MHRD of 8 mg Cardura XL. There is no evidence that similar lesions occur in humans.

Clinical Studies

Studies in Patients with BPH

Two controlled clinical studies were conducted with Cardura XL in BPH patients, followed by an open-label extension study. Study 1 was a randomized, double-blind, parallel-group, placebo- and active-controlled study that compared the safety and efficacy of Cardura XL (4 or 8 mg/day) with that of doxazosin IR (1, 2, 4, or 8 mg/day) and placebo over 13 weeks in 795 BPH patients, of whom 317 were randomized to Cardura XL. Study 2 was a randomized, double-blind, parallel-group, active-controlled study that compared the safety and efficacy of Cardura XL (4 or 8 mg/day) with that of doxazosin IR (1, 2, 4, or 8 mg/day) over 13 weeks in 680 BPH patients, of whom 350 were randomized to Cardura XL.

In both studies, men aged 50–80 years with symptomatic benign prostatic hyperplasia (BPH) were enrolled. Symptomatic BPH was defined as a total score of at least 12 points on the 35-point International Prostate Symptom Score (IPSS) and a maximum urinary flow rate of ≤ 15 mL/sec but no less than 5 mL/sec (total voided volume ≥ 150 mL). In these two studies, conducted in a total of 1475 patients, the mean age was 64 years (range 47–83 years). Patients were Caucasian (96%), Black (1.5%), Asian (1.5%), and of Other ethnicity (1%).

In both studies, Cardura XL dosing was initiated after a 2 week placebo run-in period at 4 mg per day increasing to 8 mg per day after 7 weeks of treatment if adequate response (defined as having both an increase in maximum urinary flow rate of at least 3 mL/sec and a decrease in total IPSS of at least 30% from baseline) was not seen. Doxazosin IR was titrated from an initial dose of 1 mg daily to 2 mg daily after 1 week with the option to increase to 4 mg daily after 3 weeks and then to a maximum of 8 mg daily after 7 weeks if an adequate response was not seen. The final daily dose of Cardura XL was 4 mg in 43% of patients and 8 mg in 57% of patients. The final daily dose of doxazosin IR was 1 mg in 1%, 2 mg in 12%, 4 mg in 30%, and 8 mg in 57% of patients.

There were two primary efficacy variables in each of these two controlled clinical studies: the total International Prostate Symptom Score (IPSS) and the peak urinary flow rate (Qmax). The IPSS consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible total scores ranging from 0 to 35. The Qmax was measured in both studies just prior to the next dose. The results for total symptom score are given in Table 3, and for maximum urinary flow rate in Table 4.

TABLE 3 TOTAL INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS)*

	N	MEAN BASELINE (±SD)	MEAN CHANGE (±SE)†
* Derived from IPSS questionnaire (range 0–35) † Mean change from baseline to Week 13 ‡ Statistically significant difference (p <0.001) vs. placebo
STUDY 1
Placebo	151	17.9 ± 4.3	-6.1 ± 0.41
Cardura XL	310	17.7 ± 4.3	-8.0 ± 0.30‡
Doxazosin IR	311	17.8 ± 4.5	-8.4 ± 0.29‡
STUDY 2
Cardura XL	330	18.4 ± 5.0	-8.1 ± 0.30
Doxazosin IR	313	18.4 ± 4.8	-7.9 ± 0.31

TABLE 4 MAXIMUM FLOW RATE (mL/sec)

	N	MEAN BASELINE (±SD)	MEAN CHANGE (±SE)*
* Mean change from baseline to Week 13 † Statistically significant difference (p <0.001) vs. placebo
STUDY 1
Placebo	151	9.8 ± 2.6	0.8 ± 0.32
Cardura XL	300	10.3 ± 2.6	2.6 ± 0.24†
Doxazosin IR	303	10.1 ± 2.7	2.2 ± 0.23†
STUDY 2
Cardura XL	322	10.5 ± 2.6	2.7 ± 0.27
Doxazosin IR	314	10.6 ± 2.6	2.7 ± 0.27

Mean changes in IPSS scores for Cardura XL and placebo in Study 1 are summarized in Figure 2.

Mean changes in maximum urinary flow rate (Qmax) for both Cardura XL and placebo in Study 1 are summarized in Figure 3.

How Supplied/Storage and Handling

Cardura XL (doxazosin mesylate extended release tablets) is available as 4 mg (white, imprinted with CXL 4) and 8 mg (white, imprinted with CXL 8) tablets.

Bottle of 30: 4 mg (NDC 0049-2710-30)

Bottle of 30: 8 mg (NDC 0049-2720-30)

Storage

Recommended Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Patient Counseling Information

See FDA-approved patient labeling (Patient Information)

Postural Hypotension

Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness or syncope, when beginning therapy or when increasing dosage strength of Cardura XL. Patients should be cautioned about driving, operating machinery, or performing hazardous tasks during this period, until the drug's effect has been determined.

Tablet Administration

Patients should be informed that Cardura XL extended release tablets should be swallowed whole. Patients should not chew, divide, cut, or crush tablets.

Dosing Interval

Cardura XL should be taken each day with breakfast.

Tablet Elimination

Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. In the Cardura XL extended release tablet, the medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. When this process is completed, the empty tablet is eliminated from the body.

LAB-0326-3.0

PATIENT INFORMATION

CARDURA® XL (kar-DUR-a eks el)

(doxazosin mesylate)

Tablets

Read this Patient Information leaflet before you start taking Cardura XL and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is Cardura XL?

Cardura XL is a prescription medicine called an "alpha-blocker." Cardura XL is used to treat the symptoms of benign prostatic hyperplasia (BPH). Cardura XL may help to relax the muscles in the prostate and the bladder which may lessen the symptoms of BPH and improve urine flow.

Before prescribing Cardura XL, your healthcare provider may examine your prostate gland and do a blood test called a prostate specific antigen (PSA) test to check for prostate cancer. Prostate cancer and BPH can cause the same symptoms. Prostate cancer needs a different treatment.

Some medicines called "alpha-blockers" are used to treat high blood pressure. Cardura XL is not for the treatment of high blood pressure.

It is not known if Cardura XL is safe and effective in children.

Who should not take Cardura XL?

Do not take Cardura XL if you are allergic to doxazosin, other medications called quinazolones, or any of the ingredients in Cardura XL. See the end of this leaflet for a complete list of ingredients in Cardura XL.

What should I tell my healthcare provider before taking Cardura XL?

Before you take Cardura XL, tell your healthcare provider if you:

• have or have had low blood pressure, especially after taking another medicine. Signs of low blood pressure are fainting, dizziness, and lightheadedness.


• plan to have cataract surgery


• have stomach problems


• have prostate cancer


• have liver problems


• have heart problems

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

Cardura XL may affect the way other medicines work, and other medicines may affect how Cardura XL works.

Especially tell your healthcare provider if you take:

• a medicine to treat an infection


• a medicine to treat HIV


• a medicine to treat depression


• a medicine to treat erectile dysfunction (ED)

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those listed above.

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

How should I take Cardura XL?

• Take Cardura XL exactly as your healthcare provider tells you to take it.


• Take Cardura XL 1 time each day with your breakfast.


• Take Cardura XL tablets whole. Do not chew, divide, cut, or crush Cardura XL tablets before swallowing. If you cannot swallow Cardura XL tablets whole, tell your healthcare provider. You may need a different medicine.


• Cardura XL tablets have an outside shell that helps to release the medicine inside over time. You may see the empty Cardura XL tablet in your stool (bowel movement). This is normal.


• If you take too much CARDURA XL, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking Cardura XL?

Do not drive, operate machinery, or do other dangerous activities until you know how Cardura XL affects you. Cardura XL can cause dizziness, weakness, or fainting.

What are the possible side effects of Cardura XL?

Cardura XL may cause serious side effects including:

• a sudden drop in blood pressure (postural hypotension). Postural hypotension can happen at any time while you take Cardura XL. The chance of having postural hypotension is higher a few hours after you take Cardura XL or if you start taking a higher dose.
  
  Symptoms of postural hypotension may happen after you stand up from a lying or sitting position and may include:
  
  • dizziness or
  
  
  • fainting or
  
  
  • feeling light-headed
  
  
  
  
  You should get up slowly from a chair or bed until you know how Cardura XL will affect you. If you begin to feel dizzy or lightheaded, sit or lie down with your legs and feet up. If your symptoms do not get better call your healthcare provider.


• intraoperative floppy iris syndrome (IFIS). IFIS can happen during eye surgery to people who are taking or have taken alpha-blockers such as Cardura XL. If you have an eye surgery for a clouding of the eye (cataract) planned, tell your eye doctor that you are using Cardura XL or have taken an alpha-blocker before.

The most common side effects of Cardura XL include:

• tiredness


• headache


• low blood pressure


• dizziness

Call your healthcare provider if you get any side effect that bothers you or that does not go away.

These are not all the possible side effects of Cardura XL. For more information ask your healthcare provider 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 Cardura XL?

• Store Cardura XL at 59°F to 86°F (15°C to 30°C).

Keep Cardura XL and all medicines out of reach of children.

General information about the safe and effective use of Cardura XL.

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

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

For more information, call 1-800-438-1985.

What are the ingredients in Cardura XL?

Active Ingredient: doxazosin mesylate

Inactive Ingredients: polyethylene oxide, sodium chloride, hypromellose, red ferric oxide, titanium dioxide, magnesium stearate, cellulose acetate, Macrogol®, pharmaceutical glaze, and black iron oxide.

LAB-0425-1.0

July 2011

PRINCIPAL DISPLAY PANEL - 4 mg Tablet Bottle Label

NDC 0049-2710-30

30 Tablets

Rx only

Cardura® XL

(doxazosin mesylate

extended release tablets)

4 mg*

Pfizer

Distributed by

Roerig

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY P

Germoloids Suppositories & Ointment Duo Pack

1. Name Of The Medicinal Product

Germoloids Suppositories & Ointment Duo Pack

2. Qualitative And Quantitative Composition

Suppositories Ointment

Zinc Oxide 283.5 mg 6.6% w/w

Lidocaine Hydrochloride 13.2 mg 0.7% w/w

For excipients, see section 6.1.

3. Pharmaceutical Form

Suppository for rectal administration.

Ointment for topical administration.

4. Clinical Particulars

4.1 Therapeutic Indications

The symptomatic relief of pain, swelling, irritation and itching associated with haemorrhoids and pruritus ani.

4.2 Posology And Method Of Administration

Adults and children aged 12 years and over:

Suppositories:

One suppository to be inserted into the rectum on retiring at night and in the morning, preferably after a bowel movement. If necessary the suppository may be used at any time during the day with a minimum of three to four hours between suppositories. Do not use more than four suppositories in any 24-hour period.

Ointment:

Apply to the affected area at least twice a day with a minimum of three to four hours between applications. Further applications can be made at any time of day and are particularly recommended after a bowel movement. Do not use more than four times in any 24-hour period.

Children under 12:

Only as directed by a doctor.

The elderly:

The normal adult dose may be used.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Persons who continually suffer from haemorrhoids, have severe haemorrhoids or experience excessive bleeding, are advised to consult a doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is a lack of definitive evidence of safety of the product in human pregnancy and lactation. However, lidocaine hydrochloride and zinc oxide have been in wide use for many years without apparent ill consequence. It is not necessary to contraindicate this product in pregnancy and lactation provided caution is exercised and the directions for use are followed. However, as with all medicines, the advice of a doctor should be sought.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Very rarely increased irritation may occur at the site of application when using the suppositories or the ointment.

Very rarely burning sensations may occur at the site of application when using the ointment. Rarely rashes may occur.

4.9 Overdose

It is very unlikely that overdosage would occur from these pharmaceutical forms. Symptoms of lidocaine overdosage would be unlikely to occur even after rectal insertion of large quantities.

Normally there should be no systemic adverse effects, but at worst CNS and cardiovascular effects are possible. Treatment would be symptomatic after withdrawal of the product.

In the case of accidental oral ingestion, the advice of a doctor should be sought.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Zinc oxide has astringent, antiseptic, soothing and protectant properties.

Lidocaine hydrochloride has a local anaesthetic action.

The suppository and ointment bases have lubricant and emollient properties.

5.2 Pharmacokinetic Properties

The product has a local action with minimal risk of systemic effects. Lidocaine has a fast onset and intermediate duration of action. It is partially absorbed but plasma levels will be low, in view of the concentration of lidocaine in the product. It undergoes de-ethylation in the liver, where clearance approaches the rate of hepatic flow.

5.3 Preclinical Safety Data

Preclinical safety data on the active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Suppository:

Hard fat

Methyl salicylate

Glyceryl tristearate

Ointment:

Yellow soft paraffin

Wool fat

Methyl salicylate

Propylene glycol

Menthol crystals

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25^oC.

6.5 Nature And Contents Of Container

Suppository:

Preformed PVC/polyethylene laminate moulds. Strips of suppositories are packed in a boxboard carton. Six suppositories per strip, two strips per carton.

Ointment:

a) Flexible aluminium tubes, internally lacquered, fitted with a polypropylene cap contained in a boxboard carton.

b) Aluminium laminate tube consisting of 150µm Polyethylene /5µm polyacrylate outer layer, 30µm alumininum and an inner layer of 30µm polyacrylate / 60µm polyethylene, fitted with a HD polyethylene shoulder, an aluminium/surlyn tamper evident seal, HD polypropylene cap.

Pack size: Each carton contains 12 suppositories and 15ml ointment.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Bayer plc,

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

United Kingdom

Trading as Bayer plc, Consumer Care Division.

8. Marketing Authorisation Number(S)

PL 0010/0277

9. Date Of First Authorisation/Renewal Of The Authorisation

25^th July 2006

10. Date Of Revision Of The Text

16^th June 2005

Egrifta

Pronunciation: TES-a-moe-REL-in
Generic Name: Tesamorelin
Brand Name: Egrifta

Egrifta is used for:

Reducing excess stomach fat in certain HIV-infected patients.

Egrifta is a human growth hormone-releasing factor (GRF) analog. It works by stimulating the pituitary gland to release growth hormone (GH). This causes the breakdown of excess stomach fat.

Do NOT use Egrifta if:

• you are allergic to any ingredient in Egrifta or to mannitol


• you are pregnant


• you have cancer, an underactive pituitary gland, or a pituitary gland tumor


• you have had your pituitary gland removed, pituitary gland surgery, radiation treatment of the head, or a head injury

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

Before using Egrifta:

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

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


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


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


• if you have a history of cancer, non-cancerous growths, or diabetes


• if you have severe breathing problems (eg, respiratory failure); a serious illness caused by complications from surgery, injury, or trauma; or kidney or liver problems

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

• Anticonvulsants (eg, phenytoin), corticosteroids (eg, prednisone), cyclosporine, or sex hormones (eg, estradiol, testosterone) because the risk of their side effects may be increased by Egrifta

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

How to use Egrifta:

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

• An extra patient leaflet is available with Egrifta. Talk to your pharmacist if you have questions about this information.


• Egrifta is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Egrifta at home, a health care provider will teach you how to use it. Be sure you understand how to use Egrifta. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Egrifta if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.


• Be sure to rotate your injection site on the stomach area with each dose as directed. Do not inject Egrifta into scar tissue, bruises, or the belly button.


• Do not prepare Egrifta until you are ready to use it. After mixing, use Egrifta right away and throw away any unused medicine. Do not store prepared doses for later use.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


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

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

Important safety information:

• The safety of long-term use of Egrifta is not known. Contact your doctor if your condition does not improve while you use Egrifta.


• Egrifta is not intended to manage weight loss.


• Egrifta may raise your blood sugar. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.


• Diabetes patients - Egrifta may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including IGF-I and blood sugar levels, may be performed while you use Egrifta. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Egrifta should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use Egrifta if you are pregnant. It may cause harm to the fetus. Avoid becoming pregnant while you are taking it. If you become pregnant, stop taking Egrifta and contact your doctor right away. It is not known if Egrifta is found in breast milk. Mothers infected with HIV should not breast-feed. There is a risk of passing the HIV infection or Egrifta to the baby.

Possible side effects of Egrifta:

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

Nausea; night sweats; stomach upset; trouble sleeping; vomiting.

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

Severe allergic reactions (rash; flushing; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue); arm, joint, leg, or muscle pain; burning, numbness, or tingling of the skin; decreased sense of touch; fainting or faintness; fast or irregular heartbeat; mental or mood changes (eg, depression); muscle or joint soreness or stiffness; numbness, pain, or weakness in your wrist, hand, or fingers, redness, swelling, itching, pain, irritation, rash, bleeding, or bruising at the injection site; shortness of breath or trouble breathing; swelling of the hands, ankles, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; confusion; drowsiness; flushing; rapid breathing; fruit-like breath odor).

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

See also: Egrifta side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Egrifta:

Egrifta comes with 2 boxes, one with the medicine and one with syringes, needles, and solution to mix with the medicine. Store the medicine box in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Store in original packaging until just before use. Store away from heat, moisture, and light. Do not store in the bathroom. Store the box with the solution, syringes, and needles at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Do not use Egrifta after its expiration date. Keep Egrifta out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Egrifta resources

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

• Egrifta Prescribing Information (FDA)


• Egrifta Advanced Consumer (Micromedex) - Includes Dosage Information


• Egrifta Consumer Overview


• Tesamorelin Professional Patient Advice (Wolters Kluwer)

Compare Egrifta with other medications

• Lipodystrophy

Wilate

Pronunciation: AN-tye-HEE-moe-FIL-ik FAK-tor/von WILL-a-brand FAK-tor
Generic Name: Antihemophilic Factor/von Willebrand Factor
Brand Name: Wilate

Wilate is used for:

Treating bleeding episodes in certain patients with von Willebrand disease.

Wilate is a human clotting factor complex prepared from pooled human plasma. It works by increasing the amount of clotting factor VIII and von Willebrand factor in the blood. This helps the blood to clot properly, which helps to stop bleeding.

Do NOT use Wilate if:

• you are allergic to any ingredient in Wilate (including polysorbate 80) or in the container


• you have had a severe allergic reaction (eg, rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue) to other medicines that contain antihemophilic factor or von Willebrand factor or other medicines made from human plasma

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

Before using Wilate:

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

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


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


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


• if you have a history of blood clots in the legs, lungs, or eye, or if you are at risk for developing blood clots


• if you have hemophilia A

Some MEDICINES MAY INTERACT with Wilate. However, no specific interactions with Wilate are known at this time.

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

How to use Wilate:

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

• Wilate is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Wilate at home, a health care provider will teach you how to use it. Be sure you understand how to use Wilate. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not shake Wilate. Gently swirl to mix.


• Wilate should be colorless to slightly yellow in appearance after it has been mixed. Do not use Wilate if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Use Wilate immediately after mixing. Discard any remaining solution after use.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of Wilate, contact your doctor right away.

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

Important safety information:

• Wilate may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Wilate with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Patients receiving clotting factors sometimes develop antibodies or inhibitors to the medicine. This makes it less effective. If Wilate stops working or does not work as well as it has before, contact your doctor immediately for instructions.


• Wilate is made from human blood. There is a very rare risk of getting a viral disease or a central nervous system disease called Creutzfeldt-Jakob disease from products made from human blood. Discuss any questions or concerns with your doctor. Discuss whether you should receive a hepatitis A and hepatitis B vaccine.


• Tell your doctor or dentist that you take Wilate before you receive any medical or dental care, emergency care, or surgery.


• Lab tests, including factor VIII levels and von Willebrand factor levels, may be performed while you use Wilate. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• PREGNANCY and BREAST-FEEDING: It is not known if Wilate can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Wilate while you are pregnant. It is not known if Wilate is found in breast milk. If you are or will be breast-feeding while you use Wilate, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Wilate:

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

Dizziness; mild itching at the injection site.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); burning or stinging at the injection site; calf or leg pain, redness, swelling, or tenderness; chest pain; coughing up blood; fainting; fast heartbeat; fever or chills; flushing; nausea; new or worsening bruising or bleeding; restlessness; severe or persistent dizziness or headache; shortness of breath; sluggishness; tingling; unusual weakness or fatigue; vomiting; wheezing.

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

See also: Wilate side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Wilate:

Store Wilate in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Do not use past the expiration date on the container. Wilate also may be stored at room temperature, below 77 degrees F (25 degrees C), for up to 6 months or until the expiration date, whichever occurs first. Store away from heat and light. Do not return Wilate to the refrigerator once it has been stored at room temperature. Keep Wilate out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Wilate resources

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

• Wilate Consumer Overview


• Wilate Advanced Consumer (Micromedex) - Includes Dosage Information


• Alphanate Prescribing Information (FDA)


• Humate-P Prescribing Information (FDA)

Compare Wilate with other medications

• von Willebrand's Disease

Fragmin - Extended Treatment in Oncology (5000, 7500, 10000, 12500, 15000, 18000 I.U Syringes)

1. Name Of The Medicinal Product

Single Dose Syringes

1. 

2. 

3. 

4. 

5. 

6. 

2. Qualitative And Quantitative Composition

Active ingredient

Dalteparin sodium (INN)

Quality according to Ph Eur and in-house specification

1. Fragmin 5,000 IU : Single dose syringe containing dalteparin sodium 5,000IU (anti-Factor Xa*) in 0.2ml solution for injection equivalent to 25,000IU/ml.

2. Fragmin 7,500 IU : Single dose syringe containing dalteparin sodium 7,500IU (anti-Factor Xa*) in 0.3ml solution for injection equivalent to 25,000 IU/ml.

3. Fragmin 10,000 IU : Single dose syringe containing dalteparin sodium 10,000IU (anti-Factor Xa*) in 0.4ml solution for injection equivalent to 25,000 IU/ml.

4. Fragmin 12,500 IU : Single dose syringe containing dalteparin sodium 12,500IU (anti-Factor Xa*) in 0.5ml solution for injection equivalent to 25,000 IU/ml.

5. Fragmin 15,000 IU : Single dose syringe containing dalteparin sodium 15,000IU (anti-Factor Xa*) in 0.6ml solution for injection equivalent to 25,000 IU/ml.

6. Fragmin 18,000 IU : Single dose syringe containing dalteparin sodium 18,000IU (anti-Factor Xa*) in 0.72ml solution for injection equivalent to 25,000 IU/ml.

For excipients see section 6.1.

1 – 6 : Fragmin does not contain preservatives

*Potency is described in International anti-Factor Xa units (IU) of the 1st International Standard for Low Molecular Weight Heparin.

3. Pharmaceutical Form

Solution for injection for subcutaneous administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.

4.2 Posology And Method Of Administration

Recommended dosage for adults : Single Dose Syringes

Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.

Month 1

Administer Fragmin 200 IU/kg total body weight subcutaneously (SC) once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.

Body Weight (kg)	Dose (IU)
<46	7 500
46-56	10 000
57-68	12 500
69-82	15 000
83 and over	18 000*

Maximum dose of 18, 000 IU was used in patient weighing up to 132 kg in the CLOT study.

In the case of chemotherapy-induced thrombocytopenia, Fragmin dose should be adopted as follows:

- In patients receiving Fragmin who experience platelet counts between 50,000 and 100,000/mm³, the daily dose of Fragmin should be reduced by 2,500 IU until the platelet count recovers to ³.

- In patients receiving Fragmin who experience platelet counts <50,000/mm³, Fragmin should be discontinued until the platelet count recovers above 50,000/mm³.

Months 2-6

Fragmin should be administered at a dose of approximately 150 IU/kg, subcutaneously, once daily using fixed dose syringes and the table shown below.

Body Weight (kg)	Dose (IU)
	7 500
57 to 68	10 000
69 to 82	12 500
83 to 98	15 000
	18 000

Recommended duration of treatment is 6 months (first month of Fragmin treatment is included). Relevance of continuing treatment beyond this period will be evaluated according to individual risk/benefit ratio, taking into account particularly the progression of cancer. No data is available with dalteparin beyond 6 months of treatment in the CLOT study.

In the case of chemotherapy-induced thrombocytopenia, Fragmin dose should be adopted as follows:

- With platelet counts <50,000/mm³, Fragmin dosing should be interrupted until the platelet count recovers above 50,000/mm³

- For platelet counts between 50,000 and 100,000/mm³, Fragmin should be reduced as illustrated in the table below depending on the patient's weight. Once the platelet count has recovered to ³, Fragmin should be re-instituted at full dose.

Body Weight (kg)	Scheduled Fragmin Dose (IU)	Reduced Fragmin Dose (IU)
	7 500	5 000
57 to 68	10 000	7 500
69 to 82	12 500	10 000
83 to 98	15 000	12 500
	18 000	15 000

Renal failure:

In the case of significant renal failure, defined as a creatinine clearance <30 ml/min, the dose of Fragmin should be adjusted based on anti-Factor Xa activity. If the anti-Factor Xa level is below or above the desired range, the dose of Fragmin should be increased or reduced respectively, and the anti-Factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-Factor Xa level is achieved.

As an indication, on the basis of the data available in CLOT, the observed mean levels (min, max) between 4 and 6 hours after administration in patients without severe renal insufficiency were 1.11 IU anti-Factor Xa/ml (0.6; 1.88) and 1.03 IU anti-Factor Xa/ml (0.54; 1.70), respectively, on week 1 and 4 of dalteparin 200 IU/kg OD. Anti-Factor Xa activity determinations were conducted by the chromogenic method.

For patients with an increased risk of bleeding, it is recommended that Fragmin be administered according to the twice daily regimen detailed for Fragmin 10,000 IU/ml ampoules or Fragmin Multidose Vial.

Children

Not recommended for children.

Elderly

Fragmin has been used safely in elderly patients without the need for dosage adjustment.

Method of Administration

By subcutaneous injection, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh. Patients should be supine and the total length of the needle should be introduced vertically, not at an angle, into the thick part of a skin fold, produced by squeezing the skin between thumb and forefinger; the skin fold should be held throughout the injection.

4.3 Contraindications

Known hypersensitivity to Fragmin or other low molecular weight heparins and/or heparins e.g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (type II), acute gastroduodenal ulcer; cerebral haemorrhage; known haemorrhagic diathesis; serious coagulation disorders; septic endocarditis; haemorrhagic pericardial effusion and haemorrhagic pleural effusion; injuries to and operations on the central nervous system, eyes and ears.

In patients receiving Fragmin for treatment rather than prophylaxis, local and/or regional anaesthesia in elective surgical procedures is contra-indicated with high doses of dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).

In cancer patients with body weight < 40kg at time of venous thromboembolic event, Fragmin should not be used for extended treatment of symptomatic VTE and prevention of its recurrences due to lack of data.

Dalteparin should not be used in patients who have suffered a recent (within 3 months) stroke

Unless due to systemic emboli.

4.4 Special Warnings And Precautions For Use

Do not administer by the intramuscular route. Due to the risk of haematoma, intramuscular injection of other medical preparations should be avoided when the twenty-four hour dose of dalteparin exceeds 5,000 IU.

Caution should be exercised in patients in whom there is an increased risk of bleeding complications, e.g. following surgery or trauma, haemorrhagic stroke, severe liver or renal failure, thrombocytopenia or defective platelet function, uncontrolled hypertension, hypertensive or diabetic retinopathy, patients receiving concurrent anticoagulant/antiplatelet agents (see interactions section). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).

Limited data are available regarding the safety and efficacy of antithrombotic therapy in patients with primary or metastatic tumours of the brain who develop concurrent thromboembolic events. There is a risk of fatal intracranial bleeding with use of anticoagulation in this category of patients. Therefore, if the treatment with Fragmin was considered, it should be monitored closely with regular re-assessment of the status of tumour involvement of the brain and other individual risks.

Thrombocytopenia, should it occur, usually appears within three weeks following the beginning of therapy. Therefore, it is recommended that the platelet counts are measured before starting treatment with Fragmin and monitored closely in first three weeks and regularly thereafter during treatment. Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/µl) associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of Fragmin or other low molecular weight (mass) heparins and/or heparin.

Fragmin induces only a moderate prolongation of the APTT and thrombin time. Accordingly, dosage increments based upon prolongation of the APTT may cause overdosage and bleeding. Therefore, prolongation of the APTT should only be used as a test of overdosage.

Monitoring Anti-Xa Levels

Monitoring ofAnti-Xa Levels in patients using Fragmin is not usually required but should be considered for specific patient populations such as paediatrics, those with renal failure, those who are very thin or morbidly obese, pregnant or at increased risk for bleeding or rethrombosis

Where monitoring is necessary, laboratory assays using a chromogenic substrate are considered the method of choice for measuring anti-Xa levels. Activated partial thromboplastin time (APTT) or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin. Increasing the dose of dalteparin in an attempt to prolong APTT may result in bleeding (see section 4.9 Overdosage).

Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels. Patients undergoing acute haemodialysis may be more unstable and should have a more comprehensive monitoring of anti-Xa levels (See Section 5.2 Pharmacokinetic properties).

Patients with severely disturbed hepatic function, significant renal failure or chemotherapy induced thrombocytopenia may need a reduction in dosage and should be monitored accordingly.

If a transmural myocardial infarction occurs in patients where thrombolytic treatment might be appropriate, this does not necessitate discontinuation of treatment with Fragmin but might increase the risk of bleeding.

As individual low molecular weight (mass) heparins have differing characteristics, switching to an alternative low molecular weight heparin should be avoided. The directions for use relating to each specific product must be observed as different dosages may be required.

Interchangeability with other anticoagulants

Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physico-chemical, biological, and clinical properties, leading to differences in biochemical identity, dosing and possibly clinical efficacy and safety. Each of these medicines is unique and has its own instructions for use.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

In patients undergoing spinal or epidural anaesthesia, the prophylactic use of heparin may be very rarely associated with spinal haematomas resulting in prolonged or permanent paralysis. The risk is increased by use of an epidural or spinal catheter for anaesthesia, by the concomitant use of drugs (NSAIDs), platelet inhibitors or anti-coagulants and by traumatic or repeated epidural or spinal puncture.

In decision-making on the interval between the last administration of Fragmin at prophylactic doses and the placement or removal of a peridural or spinal catheter for anaesthesia, the product characteristics and the patient profile should be taken into account. Readministration should be delayed until at least four hours after the surgical procedure is completed.

Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of peridual spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.

If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment may include spinal cord decompression.

There have been no adequate studies to assess the safe and effective use of Fragmin in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of Fragmin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. The use of Fragmin cannot be recommended for this purpose.

Paediatric Patients:

Clinical experience of treatment of children is limited. If dalteparin is used in children the anti-Xa levels should be monitored.

The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome” (see section 4.6 pregnancy and lactation).

Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The possibility of the following interactions with Fragmin should be considered:

(i) An enhancement of the anticoagulant effect by anticoagulant/antiplatelet agents e.g. aspirin/ dipyridamole, GP IIb/IIIa receptor antagonists, vitamin K antagonists, NSAIDs e.g. indometacin, cytostatics, dextran, thrombolytics, sulfinpyrazone, probenecid, and etacrynic acid.

(ii) A reduction of the anticoagulant effect may occur with concomitant administration of antihistamines, cardiac glycosides, tetracycline and ascorbic acid.

Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.

However, if there are no specific contraindications, patients with unstable coronary artery disease (unstable angina and non-Q-wave infarction) can be treated with low doses of acetylsalicylic acid.

As heparin has been shown to interact with intravenous nitroglycerine, high dose penicillin, quinine and tobacco smoking interaction cannot be ruled out for dalteparin.

4.6 Pregnancy And Lactation

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal developments, parturition or postnatal development (see Section 5.3 Preclinical Safety Data).

Only very limited controlled studies are so far available on the use of low molecular heparins in pregnancy. Dalteparin does not pass the placenta.

If dalteparin is used during pregnancy, the possibility of foetal harm appears remote. However, because the possibility of harm cannot be completely ruled out, dalteparin should be used during pregnancy only if clearly needed (see Section 5.3 Preclinical Safety Data).

Therefore, caution should be exercised when prescribing to pregnant women.

Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants (see section 4.3). In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured.

Fragmin 25000 IU/ml, solution for injection, solution, contain benzyl alcohol as a preservative. As benzyl alcohol may cross the placenta, Fragmin without preservative should therefore be used during pregnancy (see section 4.4 warnings and precautions).

Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of low molecular weight heparin. In the absence of clear dosing, efficacy and safety information in this circumstance, Fragmin is not recommended for use in pregnant women with prosthetic heart valves.

Lactation

Limited data are available for excretion of dalteparin in human milk. One study in 15 women(between day 3 and 5 of lactation and 2 to 3 hours after receiving prophylactic doses of dalteparin) detected small amounts of anti-factor Xa levels of 2 to 8% of plasma levels in breast milk, equivalent to a milk/plasma ratio of <0.025-0.224. As oral absorption of low molecular weight heparin is extremely low the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown.

A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Fragmin should be made taking into account the benefit of breast-feeding to the child and the benefit of Fragmin therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Fragmin does not affect the ability to drive or operate machinery.

4.8 Undesirable Effects

About 3% of the patients having had prophylactic treatment reported side-effects.

The reported adverse reactions, which may possibly be associated to dalteparin sodium, are listed in the following table by system organ class and frequency group: common (1/100, <1/10), uncommon (1/1000, <1/100), rare (1/10 000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse events associated with dalteparin therapy, in patients participating in controlled clinical studies were:

System Organ Class	Frequency	Adverse Reactions
Blood and lymphatic system disorders	Common   Rare	Reversible Mild non-immunologically-mediated thrombocytopenia (type I) Haemorrhage Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications – arterial and/or thrombosis or thromboembolism)
Immune system disorders	Rare	Allergic reactions
Endocrine disorders	Uncommon	Hyperkalaemia
Vascular disorders	Common	Haemorrhage (bleeding at any site)
Hepatic and biliary disorders	Common	Transient elevation of liver transaminases (ASAT, ALAT)
Skin and subcutaneous tissue disorders	Uncommon Rare	Urticaria, pruritus Skin necrosis, transient alopecia
General disorders and administration site conditions	Uncommon Common	Pain at injection site, Subcutaneous haematoma at injection site

In post-marketing experience, the following additional undesirable effects have been reported:

System Organ Class	Undesirable Effects
Immune system disorders	Anaphylactic reactions
Endocrine Disorders	Hypoaldosteronism
Nervous system disorders	Intracranial bleeds have been reported and some have been fatal
Cardiac Disorders	Prosthetic cardiac valve thrombosis
Vascular Disorders	Haemorrhage (bleeding at any site), some cases reported have been fatal
Gastrointestinal disorders	Retroperitoneal bleeds have been reported and some have been fatal
Injury, poisoning and procedural complications	Spinal or epidural haematoma

The risk of bleeding is depending on dose. Most bleedings are mild. Severe bleedings have been reported, some cases with fatal outcome.

Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see section 4.4 Special warnings and precautions for use).

Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin, the risk of osteoporosis cannot be excluded.

4.9 Overdose

The anticoagulant effect (i.e. prolongation of the APTT) induced by Fragmin is inhibited by protamine. Since protamine itself has an inhibiting effect on primary haemostasis it should be used only in an emergency.

The prolongation of the clotting time induced by Fragmin may be fully neutralised by protamine, but the anti-Factor Xa activity is only neutralised to about 25-50%. 1 mg of protamine inhibits the effect of 100 IU (anti-Factor Xa) of Fragmin.

Protamine should be given by intravenous injection over approximately 10 minutes.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code BO1 AB 04: Antithrombotics

Dalteparin sodium is a low molecular weight heparin fraction (average molecular weight 4000-6000 Daltons) produced from porcine-derived sodium heparin.

Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT).

Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system.

The randomized, open-label, controlled, multicenter CLOT study (Randomized Comparison of Low-Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer patients with Venous Thomboembolism) compared dalteparin to standard oral anticoagulant (OAC) therapy in the long term treatment of venous thromboembolism (VTE) in 676 patients with active malignancy who had experienced an acute symptomatic VTE (deep venous thrombosis (DVT) and/or a pulmonary embolism (PE)).

Patients were randomized to one of two groups:

- dalteparin arm prescribed at 200 IU/kg/day administered by subcutaneous (SC) injections (maximum 18,000 IU/day) during 1 month, then approximately 150 IU/kg/day from 2^nd– 6th month, or

- VKA arm prescribed during 6 months (target INR 2-3), preceded by SC dalteparin 200 IU/kg/day OD (maximum 18,000 IU/day) during 5 to 7 days.

The most frequent diagnoses were: tumors of the gastrointestinal tract and pancreas (23.7%), genitourinary tumors (prostate, testicle, cervix, uterus, ovary and bladder) (21.5%), breast (16.0%), lung (13.3%). 10.4% of patients had haematological malignancies ; 75.1% of patients had metastatic disease.

The index VTE event was DVT alone in nearly 70% and PE with or without DVT in 30% of patients.

The primary endpoint was the time to first recurrence of symptomatic VTE (DVT and/or PE) during 6 months.

A total of 27 patients of 338 (8.0%) in the dalteparin arm and 53 patients of 338 (15.7%) in the VKA arm experienced at least one of the events of the composite primary endpoint. A significant 52% risk reduction in VTE recurrence at 6 months was seen with dalteparin (RR= 0.48, 95% CI [0.30-0.77], p=0.0016).

In the dalteparin arm, 19 patients (5.6%) experienced at least one episode of major bleeding compared to 12 patients (3.6%) in the VKA arm. The cumulative probability of experiencing a major bleeding at 6 months was respectively 6.5% and 4.9%, respectively. Any bleeding occurred with a higher frequency in the VKA arm (18.5% VKA vs 13.6% dalteparin). The comparison of the cumulative probability of first bleeding episode for the 2 treatments was of statistical significance in favour of dalteparin treatment (p=0.0487).

There was no significant difference in mortality between the two groups in deaths at 6 and 12 months (131 vs. 137 and 190 vs. 194 in the dalteparin and VKA arms, respectively).

There was no significant difference in the assessment of Quality of Life between the two groups of treatment.

5.2 Pharmacokinetic Properties

The half life following iv and sc. administration is 2 hours and 3.5-4 hours respectively, twice that of unfractionated heparin.

The bioavailability following sc. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys.

Special Populations

Haemodialysis:

In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.

5.3 Preclinical Safety Data

The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection site, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages.

The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities.

It was concluded that dalteparin sodium may have an osteopenic effect at very high concentrations, and that this effect is less than that of unfractionated heparin at equivalent doses.

The results revealed no organ toxicity irrespective of the route of administration, doses or the duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility reproductive capacity or peri- and postnatal development was shown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

1	Fragmin 5,000 IU/0.2ml (1) Water for injections (Ph. Eur)
2	Fragmin 7,500 IU/0.3ml (2) Water for injections (Ph. Eur) Sodium hydroxide or hydrochloric acid for pH adjustment
3 – 6	Fragmin 10,000 IU/0.4ml (3) Fragmin 12,500 IU/0.5ml (4) Fragmin 15,000 IU/0.6ml (5) Fragmin 18,000 IU/0.72ml (6) Water for Injections (Ph. Eur) Sodium hydroxide or hydrochloric acid for pH adjustment

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

1	Fragmin 5,000 IU/0.2ml	36 months
2	Fragmin 7,500 IU/0.3ml	36 months
3	Fragmin 10,000 IU/0.4ml	24 months
4	Fragmin 12,500 IU/0.5ml	24 months
5	Fragmin 15,000 IU/0.6ml	24 months
6	Fragmin 18,000 IU/0.72ml	24 months

6.4 Special Precautions For Storage

1 – 6 : Store below 25^oC

6.5 Nature And Contents Of Container

1	Fragmin 5,000 IU/0.2ml Solution for Injection is supplied in 0.5ml glass Ph.Eur type I single dose syringes with chlorobutyl (Type I) rubber and polypropylene rod. Each pack contains 10 syringes.
2	Fragmin 7,500 IU/0.3ml Solution for Injection is supplied in 0.5ml glass Ph.Eur type I single dose syringes with chlorobutyl (Type I) rubber and polypropylene rod. Each pack contains 10 syringes.
3	Fragmin 10,000 IU/0.4 ml Solution for Injection is supplied in 1 ml glass Ph. Eur. Type I single dose syringes with chlorobutyl (Type I) rubber stopper and polypropylene rod. Each pack contains 5 syringes.
4	Fragmin 12,500 IU/0.5 ml solution for injection is supplied in 1 ml glass Ph. Eur. Type I single dose syringes with chlorobutyl (Type I ) rubber stopper and polypropylene rod. Each pack contains 5 syringes.
5	Fragmin 15 000 IU/0.6 ml solution for injection is supplied in 1 ml glass Ph. Eur. Type I single dose syringes with chlorobutyl (Type I ) rubber stopper and polypropylene rod. Each pack contains 5 syringes.
6	1 ml single dose syringe (glass Ph. Eur. Type I) with chlorobutyl rubber stopper containing dalteparin sodium 18,000 IU (anti-Factor Xa) in 0.72 ml. Each pack contains 5 syringes.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich KENT

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

1	PL 00057/0984
2	PL 00057/0985
3	PL 00057/0976
4	PL 00057/0980
5	PL 00057/0981
6	PL 00057/0982

9. Date Of First Authorisation/Renewal Of The Authorisation

1	:	18 March 2002
2	:	26 June 2002
3 – 6	:	18 March 2002

10. Date Of Revision Of The Text

June 2011

LEGAL CATEGORY

POM

Ref: FR 6_1