Risedronate 5mg tablets

1. Name Of The Medicinal Product

Risedronate sodium 5 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 5 mg risedronate sodium (equivalent to 4.64 mg risedronic acid).

Excipient: 0.57 mg lactose in each tablet. For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White round biconvex film-coated tablet with diameter of 6.1 mm and 2.6 mm in thickness.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prevention of osteoporosis in postmenopausal women with increased risk of osteoporosis (see section 5.1). To maintain or increase bone mass in postmenopausal women undergoing long-term (more than 3 months), systemic corticosteroid treatment at doses

4.2 Posology And Method Of Administration

The recommended daily dose in adults is one 5 mg tablet orally. The absorption of Risedronate is affected by food, thus to ensure adequate absorption patients should take Risedronate:

• Before breakfast: At least 30 minutes before the first food, other medicinal product or drink (other than plain water) of the day.

In the particular instance that before breakfast dosing is not practical, Risedronate can be taken between meals or in the evening at the same time everyday, with strict adherence to the following instructions, to ensure Risedronate is taken on an empty stomach:

• Between meals: Risedronate should be taken at least 2 hours before and at least 2 hours after any food, medicinal product or drink (other than plain water).

• In the evening: Risedronate should be taken at least 2 hours after the last food, medicinal product or drink (other than plain water) of the day. Risedronate should be taken at least 30 minutes before going to bed.

If an occasional dose is missed, Risedronate can be taken before breakfast, between meals, or in the evening according to the instructions above.

The tablets must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Risedronate is to be taken while in an upright (standing or sitting) position with a glass of plain water (

Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Elderly:

No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (>60 years of age) compared to younger subjects.

Renal impairment:

No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate sodium is contraindicated in patients with severe renal impairment (creatinine clearance lower than 30 ml/min) (see sections 4.3 and 5.2).

Children:

Safety and efficacy of risedronate 5 mg have not been established in children and adolescents.

4.3 Contraindications

Hypersensitivity to risedronate sodium or to any of the excipients.

Hypocalcaemia (see section 4.4).

Pregnancy and lactation.

Severe renal impairment (creatinine clearance <30ml/min).

4.4 Special Warnings And Precautions For Use

Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interfere with the absorption of bisphosphonates and should not be taken at the same time as Risedronate (see section 4.5) In order to achieve the intended efficacy, strict adherence to dosing recommendations is necessary (see section 4.2).

Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of low bone mineral density (BMD T-score at hip or lumbar spine <-2.5 SD) and/or prevalent fracture.

High age or clinical risk factors for fracture alone are not reasons to initiate treatment of osteoporosis with a bisphosphonate. The evidence to support efficacy of bisphosphonates including Risedronate in very elderly women (>80 years) is limited (see section 5.1).

Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Thus caution should be used:

• In patients who have a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia.

• In patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet.

• If risedronate is given to patients with active or recent oesophageal or upper gastrointestinal problems.

Prescribers should emphasise to patients the importance of paying attention to the dosing instructions and be alert to any signs or symptoms of possible oesophageal reaction. The patients should be instructed to seek timely medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.

Hypocalcaemia should be treated before starting Risedronate therapy. Other disturbances of bone and mineral metabolism (e.g. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Risedronate therapy.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphophonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit /risk assessment.

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interaction studies have been performed, however no clinically relevant interactions with other medicinal products were found during clinical trials. In the Risedronate Phase III osteoporosis studies, acetylsalicylic acid or NSAID use was reported by 33% and 45% of patients respectively.

If considered appropriate Risedronate may be used concomitantly with oestrogen supplementation.

Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interfere with the absorption of Risedronate (see section 4.4).

Risedronate is not systemically metabolised, does not induce cytochrome P450 enzymes, and has low protein binding.

4.6 Pregnancy And Lactation

There are no adequate data from the use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Studies in animal indicate that a small amount of risedronate sodium pass into breast milk.

Risedronate sodium must not be used during pregnancy or by breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable Effects

Risedronate has been studied in phase III clinical trials involving more than 15,000 patients.

The majority of undesirable effects observed in clinical trials was mild to moderate in severity and usually did not require cessation of therapy.

Adverse experiences reported in phase III clinical trials in postmenopausal women with osteoporosis treated for up to 36 months with risedronate 5mg/day (n=5020) or placebo (n=5048) and considered possibly or probably related to risedronate are listed below using the following convention (incidences versus placebo are shown in brackets):

Very common (

Nervous system disorders:

Common: headache (1.8% vs. 1.4%).

Eye disorders:

Uncommon: iritis.*

Gastrointestinal disorders:

Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs. 4.0%), abdominal pain (3.5% vs. 3.3%), diarrhoea (3.0% vs. 2.7%).

Uncommon: gastritis (0.9% vs. 0.7%), oesophagitis (0.9% vs. 0.9%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1%), oesophageal ulcer (0.2% vs. 0.2%)

Rare: glossitis (<0.1% vs. 0.1%), oesophageal stricture (<0.1% vs. 0.0%).

Musculoskeletal and connective tissues disorders:

Common: musculoskeletal pain (2.1% vs. 1.9%).

Investigations:

Rare: abnormal liver function tests.*

* No relevant incidences from Phase III osteoporosis studies; frequency based on adverse event/laboratory/rechallenge findings in earlier clinical trials.

Laboratory findings: Early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels have been observed in some patients.

The following additional adverse reactions have been reported during post-marketing use (frequency unknown):

Eye disorders:

iritis, uveitis.

Musculoskeletal and connective tissues disorders:

osteonecrosis of the jaw.

Skin and subcutaneous tissue disorders:

hypersensitivity and skin reactions, including angioedema, generalised rash, urticaria, bullous skin reactions and leukocytoclastic vasculitis, some severe including isolated reports of Stevens Johnson syndrome and toxic epidermal necrolysis.

hair loss.

Immune system disorders:

anaphylactic reaction

Hepatobiliary disorders:

serious hepatic disorders. In most of the reported cases the patients were also treated with other products known to cause hepatic disorders.

4.9 Overdose

No specific information is available on the treatment of overdose with risedronate sodium.

Decreases in serum calcium following substantial overdose may be expected. Signs and symptoms of hypocalcaemia may also occur in some of these patients

Milk or antacids containing magnesium, calcium or aluminium should be given to bind risedronate and reduce absorption of risedronate sodium. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Bisphosphonates

ATC Code: M05 BA07

Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation is preserved. In preclinical studies risedronate sodium demonstrated potent anti-osteoclast and antiresorptive activity, and dose dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. Decreases in biochemical markers of bone turnover were observed within 1 month and reached a maximum in 3-6 months.

Treatment and Prevention of Postmenopausal Osteoporosis:

A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.

The clinical programme studied the effect of risedronate sodium on the risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily doses of 2.5 mg and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if baseline levels were low). The absolute and relative risk of new vertebral and hip fractures were estimated by use of a time-to-first event analysis.

• Two placebo-controlled trials (n=3,661) enrolled postmenopausal women under 85 years with vertebral fractures at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49% and 41% respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo 29.0% and 16.3%, respectively). The effect of treatment was seen as early as the end of the first year of treatment. Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also reduced the yearly height loss compared to the control group.

• Two further placebo controlled trials enrolled postmenopausal women above 70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD T-score < -3 SD (manufacturer's range, i.e. -2.5 SD using NHANES III) and at least one additional risk factor. Women a-posteriori analysis of subgroups defined by clinical practise and current definitions of osteoporosis:

- In the subgroup of patients with femoral neck BMD T-score < -2.5SD (NHANES III) and at least one vertebral fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control group (incidence of hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo 7.4%).

- Data suggest that a more limited protection than this may be observed in the very elderly (>80 years). This may be due to the increasing importance of non-skeletal factors for hip fracture with increasing age. In these trials, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in patients with low femoral neck BMD without vertebral fracture and in patients with low femoral neck BMD with or without vertebral fracture.

- Risedronate sodium 5 mg daily given for 3 years increased bone mineral density (BMD) relative to control at the lumbar spine, femoral neck, trochanter and wrist and prevented bone loss at the mid-shaft radius.

- In a one-year follow-up off therapy after three years treatment with risedronate sodium 5 mg daily there was rapid reversibility of the suppressing effect of risedronate sodium on bone turnover rate.

- In postmenopausal women taking oestrogen, risedronate sodium 5 mg daily increased bone mineral density (BMD) at the femoral neck and mid-shaft radius only, compared to oestrogen alone.

- Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2 to 3 years, showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality.

- Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both risedronate sodium and control patients indicated no evidence of treatment related gastric, duodenal or oesophageal ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group.

- In a trial comparing before-breakfast dosing and dosing at other times of the day in women with postmenopausal osteoporosis, lumbar spine BMD gains were statistically higher with before-breakfast dosing.

In osteoepenic postmenopausal women, risedronate sodium has shown superiority to placebo in increasing lumbar spine BMD at 12 and 24 months.

Corticosteroid Induced Osteoporosis: The clinical programme included patients initiating corticosteroid therapy (

• Risedronate sodium 5 mg daily given for one year maintains or increases bone mineral density (BMD) relative to control at the lumbar spine, femoral neck, and trochanter.

• Risedronate sodium 5 mg daily reduced the incidence of vertebral fractures, monitored for safety, relative to control at 1 year in pooled studies.

• Histological examination of bone biopsies from patients taking corticosteroids and risedronate sodium 5 mg daily did not show signs of disturbed mineralisation process.

5.2 Pharmacokinetic Properties

Absorption: Absorption after an oral dose is relatively rapid (t_max ~1 hour) and is independent of dose over the range studied (2.5 to 30 mg). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women.

Distribution: The mean steady state volume of distribution is 6.3 l/kg in humans. Plasma protein binding is about 24%.

Metabolism: There is no evidence of systemic metabolism of risedronate sodium.

Elimination: Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine after 28 days. Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with the difference probably attributed to clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration the concentration-time profile shows three elimination phases with a terminal half-life of 480 hours.

Special populations:

Elderly: no dosage adjustment is necessary.

Acetylsalicylic acid/NSAID users: Among regular acetylsalicylic acid or NSAID users (3 or more days per week) the incidence of upper gastrointestinal adverse events in Risedronate treated patients was similar to that in control patients.

5.3 Preclinical Safety Data

In toxicological studies in rat and dog dose dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in longer term studies in rodents, although the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcaemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2mg/kg/day in rat and 10mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Studies on genotoxicity and carcinogenesis did not show any particular risks for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Starch, pregelatinised (maize); Cellulose, microcrystalline; Crospovidone; Magnesium stearate.

Film coating:

Hypromellose; Lactose monohydrate; Titanium dioxide (E171); Macrogol 4000.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Nature of container: Opaque PVC/PE/PVDC/Aluminium blister in a carton box.

Pack sizes: 14, 28, 84, 98 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Beacon Pharmaceuticals Ltd., 85 High St., Tunbridge Wells, TN1 1YG. UK.

8. Marketing Authorisation Number(S)

PL 18157/0233

9. Date Of First Authorisation/Renewal Of The Authorisation

03/08/2010

10. Date Of Revision Of The Text

03/08/2010

Augmentin XR

amoxicillin and clavulanate potassium

Dosage Form: tablet, film coated, extended release
Augmentin XR®

(amoxicillin/clavulanate potassium)

Extended Release Tablets

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN XR (amoxicillin/clavulanate potassium) and other antibacterial drugs, AUGMENTIN XR should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Augmentin XR Description

Augmentin XR is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) and the β-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus 6-aminopenicillanic acid. The amoxicillin trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45. Chemically, amoxicillin trihydrate is (2S,5R ,6R)-6-[(R ) - ( - ) - 2 - Amino - 2 - (p - hydroxyphenyl)acetamido] - 3,3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo[3.2.0]heptane - 2 - carboxylic acid trihydrate and may be represented structurally as:

The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39. Chemically, amoxicillin sodium is [2S-[2α,5α,6β(S *)]] - 6 - [[Amino(4 - hydroxyphenyl)acetyl]amino] - 3,3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo[3.2.0]heptane - 2 - carboxylic acid monosodium salt and may be represented structurally as:

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)-(2R ,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:

Inactive Ingredients

Citric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum.

Each tablet of Augmentin XR contains 12.6 mg (0.32 mEq) of potassium and 29.3 mg (1.27 mEq) of sodium.

Augmentin XR - Clinical Pharmacology

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Augmentin XR.

Augmentin XR is an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with Augmentin XR is similar to that produced by the oral administration of equivalent doses of amoxicillin alone. In a study of healthy adult volunteers, the pharmacokinetics of Augmentin XR were compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89.3 g carb, 24.9 g fat, and 14.0 g protein), or 30 minutes after a high-fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, Augmentin XR is optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state. Augmentin XR is not recommended to be taken with a high-fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of Augmentin XR following administration of two Augmentin XR tablets at the start of a standardized meal are presented in Table 1.

Table 1. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Augmentin XR Tablets (2,000 mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal

Parameter (units)	Amoxicillin	Clavulanate
AUC(0-inf) (mcg•hr/mL)	71.6 (16.5)	5.29 (1.55)
Cmax (mcg/mL)	17.0 (4.0)	2.05 (0.80)
Tmax (hours)a	1.50 (1.00 - 6.00)	1.03 (0.75 - 3.00)
T½ (hours)	1.27 (0.20)	1.03 (0.17)

a  Median (range).

The half-life of amoxicillin after the oral administration of Augmentin XR is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.

Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a non-renal component.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanate.

In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by administration of an antacid (MAALOX®), either simultaneously with or 2 hours after Augmentin XR.

Neither component in Augmentin XR is highly protein-bound; clavulanate has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of AUGMENTIN XR 2000 mg/125 mg (as two 1000 mg/62.5 mg tablets) every 12 hours with food (Table 2).

Table 2. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two AUGMENTIN XR Tablets (2,000 mg/125 mg) Every 12 Hours With Food to Pediatric Patients (7 to 15 Years of Age and Weighing ≥ 40kg) With Acute Bacterial Sinusitis

Parameter (units)	Amoxicillin (n=24)	Clavulanate (n=23)
AUC(0-τ) (mcg•hr/mL)	57.8 (15.6)	3.18 (1.37)
Cmax (mcg/mL)	11.0 (3.34)	1.17 (0.67)
Tmax (hours)a	2.0 (1.0 – 5.0)	2.0 (1.0 – 4.0)
T½ (hours)	3.32 (2.21)b	0.94 (0.13)c

a  Median (range).

b  n=18.

c  n=17.

Microbiology

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases, and therefore, its spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a β-lactam, structurally related to penicillin, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently found responsible for transferred drug resistance.

The clavulanic acid component of Augmentin XR protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibiotics.

Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Streptococcus pneumoniae (including isolates with penicillin MICs ≤ 2 mcg/mL)

Staphylococcus aureus (including β-lactamase−producing isolates)

NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae (including β-lactamase−producing isolates)

Moraxella catarrhalis (including β-lactamase−producing isolates)

Haemophilus parainfluenzae (including β-lactamase−producing isolates)

Klebsiella pneumoniae (all known isolates are β-lactamase−producing)

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid.1,2 However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Streptococcus pyogenes

Anaerobic Microorganisms

Bacteroides fragilis (including β-lactamase−producing isolates)

Fusobacterium nucleatum (including β-lactamase−producing isolates)

Peptostreptococcus magnus

Peptostreptococcus micros

NOTE:S. pyogenes, P. magnus, and P. micros do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to S. pyogenes.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Technique

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.1,3 Standardized procedures are based on dilution methods (broth or agar; broth for S. pneumoniae and H. influenzae) or equivalent with standardized inoculum concentration and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobials. One such standardized technique requires the use of a standardized inoculum concentration.1,4 This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate potassium. Disk diffusion zone sizes should be interpreted according to criteria provided in Table 3.

Table 3. Susceptibility Test Result Interpretive Criteria for Amoxicillin/Clavulanate Potassium

	Minimum Inhibitory Concentration (mcg/mL)			Disk Diffusion (Zone Diameter in mm)
Pathogen	S	I	R	S	I	R
Haemophilus spp.	≤ 4/2	Not applicable (NA)	≥ 8/4	≥ 20	NA	≤ 19
Klebsiella pneumoniae	≤ 8/4	16/8	≥ 32/16	≥ 18	14 to 17	≤ 13
Staphylococcus spp.	≤ 4/2	NA	≥ 8/4	≥ 20	NA	≤ 19
Streptococcus pneumoniae (non-meningitis isolates)	≤ 2/1	4/2	≥ 8/4	NA

NOTE: Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20 mm are susceptible to amoxicillin/clavulanate acid. An amoxicillin/clavulanate acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤ 19 mm.

NOTE: β-lactamase−negative, ampicillin-resistant H. influenzae isolates must be considered resistant to amoxicillin/clavulanic acid.

A report of S (“Susceptible”) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of I (“Intermediate”) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high doses of antimicrobial can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures.1,3,4 Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges for the quality control organisms in Table 4. For the disk diffusion technique, the 30 mcg amoxicillin/clavulanate potassium disk should provide the zone diameter ranges for the quality control organisms in Table 4.

Table 4. Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium

Quality Control Organism	Minimum Inhibitory Concentration Range (mcg/mL)	Disk Diffusion (Zone Diameter Range in mm)
Escherichia coli ATCC®a 35218b (H. influenzae quality control)	4/2 to 16/8	17 to 22
Escherichia coli ATCC 25922	2/1 to 8/4	18 to 24
Haemophilus influenzae ATCC 49247	2/1 to 16/8	15 to 23
Staphylococcus aureus ATCC 29213	0.12/0.06 to 0.5/0.25	Not applicable (NA)
Staphylococcus aureus ATCC 25923	NA	28 to 36
Streptococcus pneumoniae ATCC 49619	0.03/0.015 to 0.12/0.06	NA

a  ATCC is a trademark of the American Type Culture Collection.

b  When using Haemophilus Test Medium (HTM).

Indications and Usage for Augmentin XR

Augmentin XR Extended Release Tablets are indicated for the treatment of patients with community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase−producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae, or methicillin-susceptible S. aureus) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs = 2 mcg/mL). Augmentin XR is not indicated for the treatment of infections due to S. pneumoniae with penicillin MICs ≥ 4 mcg/mL. Data are limited with regard to infections due to S. pneumoniaewith penicillin MICs ≥ 4 mcg/mL (see CLINICAL STUDIES).

Of the common epidemiological risk factors for patients with resistant pneumococcal infections, only age > 65 years was studied. Patients with other common risk factors for resistant pneumococcal infections (e.g., alcoholism, immune-suppressive illness, and presence of multiple co-morbid conditions) were not studied.

In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae is suspected, bacteriological studies should be performed to determine the causative organisms and their susceptibility when Augmentin XR is prescribed.

Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S. pneumoniae plus a β-lactamase−producing pathogen can be treated with another AUGMENTIN® (amoxicillin/clavulanate potassium) product containing lower daily doses of amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours). Acute bacterial sinusitis or community-acquired pneumonia due to S. pneumoniae alone can be treated with amoxicillin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN XR and other antibacterial drugs, AUGMENTIN XR should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Augmentin XR is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium.

Augmentin XR is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min.) and in hemodialysis patients.

Warnings

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH Augmentin XR, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, Augmentin XR SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Augmentin XR, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Augmentin XR should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications (see CONTRAINDICATIONS and ADVERSE REACTIONS—Liver).

Precautions

General

While amoxicillin/clavulanate potassium possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable if therapy is for longer than the drug is approved for administration.

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas spp. or Candida spp.), the drug should be discontinued and/or appropriate therapy instituted.

Prescribing AUGMENTIN XR in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Augmentin XR should be taken every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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

Drug Interactions

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Augmentin XR may result in increased and prolonged blood levels of amoxicillin. Coadministration of probenecid cannot be recommended.

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported rarely in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. In controlled clinical trials of Augmentin XR, 25 patients received concomitant allopurinol and Augmentin XR. No rashes were reported in these patients. However, this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant Augmentin XR and allopurinol use.

In common with other broad-spectrum antibiotics, Augmentin XR may reduce the efficacy of oral contraceptives.

Drug/Laboratory Test Interactions

Oral administration of Augmentin XR will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin and therefore Augmentin XR, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin, and therefore, Augmentin XR.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of AUGMENTIN was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay, where weak activity was found at very high, cytotoxic concentrations. AUGMENTIN at oral doses of up to 1,200 mg/kg/day (1.9 times the maximum human dose of amoxicillin and 15 times the maximum human dose of clavulanate based on body surface area) was found to have no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Pregnancy

Teratogenic Effects

Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given AUGMENTIN at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus due to AUGMENTIN. In terms of body surface area, the doses in rats were 1.6 times the maximum human oral dose of amoxicillin and 13 times the maximum human dose for clavulanate. For mice, these doses were 0.9 and 7.4 times the maximum human oral dose of amoxicillin and clavulanate, respectively. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Oral ampicillin-class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of Augmentin XR in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with AUGMENTIN may be associated with an increased risk of necrotizing enterocolitis in neonates.

Nursing Mothers

Ampicillin-class antibiotics are excreted in the milk; therefore, caution should be exercised when Augmentin XR is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Augmentin XR have been established for pediatric patients weighing ≥ 40 kg who are able to swallow tablets. Use of Augmentin XR in these pediatric patients is supported by evidence from adequate and well-controlled trials of adults with acute bacterial sinusitis and community-acquired pneumonia with additional data from a pediatric pharmacokinetic study.

A pharmacokinetic study in pediatric patients (7 to 15 years of age and weighing ≥ 40 kg) was conducted (see CLINICAL PHARMACOLOGY).

The adverse event profile in 44 pediatric patients who received at least one dose of Augmentin XR was consistent with the established adverse event profile for the product in adults.

Geriatric Use

Of the total number of subjects in clinical studies of Augmentin XR, 18.4% were 65 years or older and 7.2% were 75 years or older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other clinical experience has not reported differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of dose-dependent toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

Each tablet of Augmentin XR contains 29.3 mg (1.27 mEq) of sodium.

Adverse Reactions

In clinical trials, 5,643 patients have been treated with Augmentin XR. The majority of side effects observed in clinical trials were of a mild and transient nature; 2% of patients discontinued therapy because of drug-related side effects. The most frequently reported adverse effects which were suspected or probably drug-related were diarrhea (14.5%), vaginal mycosis (3.3%) nausea (2.1%), and loose stools (1.6%). Augmentin XR had a higher rate of diarrhea which required corrective therapy (3.8% versus 2.6% for Augmentin XR and all comparators, respectively).

The following adverse reactions have been reported for ampicillin-class antibiotics:

Gastrointestinal

Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS).

Hypersensitivity Reactions

Skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin (see WARNINGS).

Liver

A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, (see CONTRAINDICATIONS), increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with AUGMENTIN or Augmentin XR. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications.

Renal

Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).

Hemic and Lymphatic Systems

Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.

Central Nervous System

Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, headache, insomnia, and reversible hyperactivity have been reported rarely.

Miscellaneous

Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

Overdosage

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In the case of overdosage, discontinue Augmentin XR, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.5

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.

Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis (see DOSAGE AND ADMINISTRATION).

Augmentin XR Dosage and Administration

Augmentin XR should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Absorption of the amoxicillin component is decreased when Augmentin XR is taken on an empty stomach (see CLINICAL PHARMACOLOGY).

The recommended dose of Augmentin XR is 4,000 mg/250 mg daily according to the following table:

Indication	Dose	Duration
Acute bacterial sinusitis	2 tablets q12h	10 days
Community-acquired pneumonia	2 tablets q12h	7-10 days

Tablets of AUGMENTIN (250 mg or 500 mg) CANNOT be used to provide the same dosages as Augmentin XR Extended Release Tablets. This is because AUGMENTIN XR contains 62.5  mg of clavulanic acid, while the AUGMENTIN 250-mg and 500-mg tablets each contain 125 mg of clavulanic acid. In addition, the Extended Release Tablet provides an extended time course of plasma amoxicillin concentrations compared to immediate-release Tablets. Thus, two AUGMENTIN 500-mg tablets are not equivalent to one Augmentin XR tablet.

Scored Augmentin XR Extended Release Tablets are available for greater convenience for adult patients who have difficulty swallowing. The scored tablet is not intended to reduce the dosage of medication taken; as stated in the table above, the recommended dose of Augmentin XR is two tablets twice a day (every 12 hours).

Renally Impaired Patients

The pharmacokinetics of Augmentin XR have not been studied in patients with renal impairment. Augmentin XR is contraindicated in patients with a creatinine clearance of < 30 mL/min. and in hemodialysis patients (see CONTRAINDICATIONS).

Hepatically Impaired Patients

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals (see WARNINGS).

Pediatric Use

Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose.

Geriatric Use

No dosage adjustment is required for the elderly (see PRECAUTIONS, Geriatric Use).

HOW SUPPLIED

Augmentin XR Extended Release Tablets

Each white, oval film-coated bilayer scored tablet, debossed with Augmentin XR, contains amoxicillin trihydrate and amoxicillin sodium equivalent to a total of 1,000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid.

NDC 43598-020-28     Bottles of 28 (7 day XR pack)

NDC 43598-020-40     Bottles of 40 (10 day XR pack)

STORAGE

Store tablets at or below 25°C (77°F). Dispense in original container.

CLINICAL STUDIES

Acute Bacterial Sinusitis

Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either Augmentin XR 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17-28) visit. The combined clinical and radiological responses were 83.7% for Augmentin XR and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and 88.6%, respectively.

The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of Augmentin XR (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations).

Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials. Microbiologic eradication rates for key pathogens in these studies are shown in the following table:

TachoSil Patch

Dosage Form: patch
FULL PRESCRIBING INFORMATION

Indications and Usage for TachoSil Patch

TachoSil is indicated as an adjunct to hemostasis for use in cardiovascular surgery when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical.

Limitations of TachoSil Use

• Do not use TachoSil in renal pelvis or ureter procedures because it may become potential foci for calculus formation.


• Do not use TachoSil in the closure of skin incisions because it may interfere with the healing of skin edges or cause wound dehiscence.


• Do not use TachoSil in neurosurgical procedures as safety and efficacy has not been evaluated in neurosurgery.

TachoSil Patch Dosage and Administration

• Apply on the surface of tissue only. Do not use intravascularly.


• The number of TachoSil Patches to be applied should be determined by the size of the bleeding area to be treated.


• Apply the yellow, active side of the patch to the bleeding area.


• Do not exceed 7 patches sized 9.5 × 4.8 cm, 14 patches sized 4.8 × 4.8 cm, or 42 patches sized 3.0 × 2.5 cm. (See Table 1 under (See DOSAGE FORMS AND STRENGTHS (3) and WARNINGS AND PRECAUTIONS, Closed Spaces (5.5)).

Preparation for Application of TachoSil Patch

• TachoSil comes ready to use in sterile packages and must be handled accordingly. Use only undamaged packages as resterilization is not possible.


• When in the operating room, the outer aluminum foil pouch may be opened in a non-sterile environment (Fig. 1A). The inner sterile blister must be opened in a sterile environment (Fig. 1B).


• Remove the TachoSil Patch from the blister (Fig. 1C), which can be used as a container for premoistening of the patch, if needed.


• Tailor the selection and application of TachoSil according to the size of the bleeding area. Select the appropriate TachoSil Patch so that it extends 1 - 2 cm beyond the margins of the wound. The patch can be cut to the correct size and shape if desired (Fig. 1D). If more than one patch is used, overlap patches by at least 1 cm.

Figure 1: Pictures illustrating steps for preparation for application of TachoSil

A	B	C	D

Method of Application

• Prior to application, cleanse the area to be treated to remove disinfectants and other fluids. The fibrinogen and thrombin proteins can be denatured by alcohol, iodine or heavy metal ions. If any of these substances have been used to clean the wound area, thoroughly irrigate the area before the application of TachoSil.


• Apply TachoSil directly to the bleeding area either wet or dry. If applied wet, pre-moisten TachoSil in 0.9% saline solution for no more than 1 minute and then apply immediately. In the case of a wet tissue surface (e.g., oozing bleeding) TachoSil may be applied without pre-moistening.


• Apply the yellow, active side of the patch to the bleeding area (Fig. 2A) and hold in place with gentle pressure applied through moistened gloves or a moist pad for at least 3 minutes (Fig. 2B).


• When applying TachoSil, use precaution because the white, inactive side of TachoSil may also adhere to surgical instruments (e.g., forceps) or gloves covered with blood due to the affinity of collagen to blood. Pre-moisten surgical instruments and gloves with saline solution to reduce the adherence.


• After gently holding TachoSil to the bleeding area for at least 3 minutes, remove the gloved hand or moistened pad carefully from the patch. To avoid pulling the patch loose, first place a pre-moistened surgical instrument at one end of the patch before relieving the pressure (Fig. 2C). Gentle irrigation may also aid in removing the premoistened pad or glove hand without removing TachoSil from the bleeding area.


• Leave TachoSil in place once it adheres to organ tissue. Remove unattached TachoSil Patches (or part of) and replace with new patches.


• TachoSil cannot be resterilized once removed from inner pouch. Discard unused, opened packages of TachoSil.

Figure 2: Pictures illustrating steps for method of application of TachoSil

A	B	C

For record-keeping purposes, record patient name and TachoSil batch number every time that TachoSil is administered to a patient.

Dosage Forms and Strengths

Each patch is packaged in an appropriately sized blister pack of polystyrene formed foil and grid varnish coated medicinal paper and overwrapped with an aluminum laminate foil pack with a desiccant bag.

Each TachoSil Patch is packaged individually and is supplied in the following pack sizes:

• Package with 1 patch of 9.5 cm × 4.8 cm


• Package with 2 patches of 4.8 cm × 4.8 cm


• Package with 1 patch of 3.0 cm × 2.5 cm


• Package with 5 patches of 3.0 cm × 2.5 cm

Strength: Each square centimeter of TachoSil contains:

Human fibrinogen	3.6 – 7.4 mg (5.5 mg)
Human thrombin	1.3 – 2.7 Units (2.0 U)

When applying TachoSil, do not exceed the maximum number of TachoSil Patches shown in Table 1 (See WARNINGS AND PRECAUTIONS, Closed Spaces (5.5)).

Table 1 Amount of Fibrinogen and Thrombin per total patch size and maximum number of patches to be applied

TachoSil Patch Size	Amount of Human Fibrinogen/Total Patch Size (mg)	Amount of Human Thrombin/Total Patch Size (Units)	Maximum Number of TachoSil Patches to be Applied
9.5 cm × 4.8 cm	337.4	123.1	7
4.8 cm × 4.8 cm	170.5	62.2	14
3.0 cm × 2.5 cm	55.5	20.3	42

Additional inactive ingredients: Equine collagen, human albumin, riboflavin (E 101), sodium chloride, sodium citrate, L-arginine hydrochloride.

Contraindications

Intravascular Application

Do not apply TachoSil intravascularly. Intravascular application of TachoSil may result in life-threatening thromboembolic events (See ADVERSE REACTIONS, Post Marketing Experience (6.2)).

Hypersensitivity

Do not use TachoSil in individuals known to have anaphylactic or severe systemic reaction to human blood products or horse proteins (See ADVERSE REACTIONS, Post Marketing Experience (6.2)).

Warnings and Precautions

Arterial Bleeding

Do not use TachoSil for the treatment of severe or brisk arterial bleeding because TachoSil has not been evaluated in this treatment.

Primary Hemostasis

Do not use TachoSil as the primary mode to control hemostasis. TachoSil is not intended as a substitute for meticulous surgical technique and the proper application of suture, ligature or other conventional procedures for hemostasis.

Hypersensitivity/Allergic/Anaphylactic Reactions

Hypersensitivity or allergic/anaphylactoid reactions may occur with TachoSil. Symptoms associated with allergic anaphylactic reactions include: flush, urticaria, pruritus, nausea, drop in blood pressure, tachycardia or bradycardia, dyspnea, severe hypotension and anaphylactic shock. These reactions may occur in patients receiving TachoSil for the first time or may increase with repetitive applications of TachoSil.

In the event of hypersensitivity reactions, discontinue administration of TachoSil. Mild reactions can be managed with antihistamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.

Contaminated Spaces

Do not leave TachoSil in an infected or contaminated space because it may potentiate an existing infection.

Closed Spaces

When placing TachoSil into cavities or closed spaces, avoid over-packing because this may cause compression of underlying tissue. Use only the minimum amount of TachoSil Patches necessary to achieve hemostasis (See DOSAGE FORM AND STRENGTHS (3)). Carefully remove or reposition unattached pieces of TachoSil, if medically necessary (See DOSAGE AND ADMINISTRATION, Method of Application (2.2)).

Transmissible Infectious Agents

The active substances of TachoSil are made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating and removing certain viruses (see 11 DESCRIPTION). Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, telephone # 1-800-423-2862. The physician should discuss the risks and benefits of this product with the patient.

Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection), immune-compromised individuals or individuals with an increased erythropoiesis (e.g. hemolytic anemia). (See USE IN SPECIAL POPULATIONS, Pregnancy (8.1) and PATIENT COUNSELING INFORMATION (17))

Adverse Reactions

The most common adverse reactions reported in > 5% of patients were atrial fibrillation and pyrexia. Atrial fibrillation was reported in 6.1% of TachoSil cases (5.9% of controls) and pyrexia in 5.8% of TachoSil cases (4.9% of controls).

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 practice.

In the cardiovascular study the most frequently reported adverse reactions were atrial fibrillation (18 patients [29.0%] in the TachoSil group and 14 patients [24.6%] in the comparator group) and pleural effusion (14 patients [22.6%] in the TachoSil group and 11 patients [19.3%] in the comparator group), see Table 2.

Table 2 Clinically Relevant Adverse Reactions Reported in at Least 5% of Patients in Either Treatment Group (cardiovascular study), Irrespective of Causality

Adverse Reaction (Preferred Term)	TachoSil N = 62* n (%)	Comparator N = 57* n (%)
* As treated population (safety data set). † The table presents the number of patients experiencing at least 1 adverse reaction (regardless of causality. At each level of patient summarization, please note that a patient is counted once regardless of whether the patient had one or more events reported.
At least 1 adverse event†	46 (74.2%)	43 (75.4%)
Atrial fibrillation	18 (29.0%)	14 (24.6%)
Pleural effusion	14 (22.6%)	11 (19.3%)
Hemorrhagic anemia	5 (8.1%)	6 (10.5%)
Tachyarrhythmia	4 (6.5%)	4 (7.0%)
Pyrexia	4 (6.5%)	3 (5.3%)
Pericardial effusion	3 (4.8%)	4 (7.0%)
Post procedural hemorrhage	3 (4.8%)	3 (5.3%)

Post Marketing Experience

The following adverse reactions have been reported in post marketing experience with TachoSil in the EU and could reasonably be expected to occur with TachoSil in the US:

General disorders and administration site conditions: drug ineffective, inflammation, granuloma, catheter related complication, multiorgan failure, pyrexia

Injury, poisoning and procedural complications: post procedural hemorrhage, foreign body trauma, post procedural pulmonary embolism

Vascular disorders: phlebitis, hematoma, hemorrhage, thrombosis

Infections and infestations: hepatitis C, abscess

Respiratory, thoracic and mediastinal disorders: respiratory distress, laryngeal edema, hemothorax

Blood and lymphatic system disorders: splenic hemorrhage, eosinophilia

Hepatobiliary disorders: biloma, portal vein thrombosis

Renal and urinary disorders: renal artery thrombosis, renal failure

Endocrine disorders: parathyroid disorder

Eye disorders: mydriasis

Nervous system disorders: nerve compression

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Drug Interactions

No drug interactions are known.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with TachoSil. There are no adequate and well-controlled studies in pregnant women. It is also not known whether TachoSil can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection). TachoSil should be administered to pregnant women only if clearly needed (see PATIENT COUNSELING INFORMATION (17)).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TachoSil is administered to nursing mothers.

Pediatric Use

The safety and effectiveness of TachoSil in pediatric patients undergoing cardiovascular surgery have not been established.

Geriatric Use

Clinical trials included 219 patients older than 65 years of age receiving TachoSil. No overall differences in safety or effectiveness were observed between the elderly and younger patients. However, greater susceptibility of some older patients to adverse reactions cannot be ruled out.

TachoSil Patch Description

TachoSil is a fibrin sealant patch consisting of an off-white, closed cell, equine collagen sponge coated on one side with two active ingredients: human fibrinogen and human thrombin. Riboflavin is included in the coating mixture as a yellow colorant to signify the active surface. Each square centimeter contains approximately 5.5 mg of human fibrinogen and 2.0 units of human thrombin. Other inactive ingredients include equine collagen, human albumin, sodium chloride, sodium citrate and L-arginine hydrochloride.

Each patch is packaged in an appropriately sized blister pack of polystyrene formed foil and grid varnish coated medicinal paper and overwrapped with an aluminum laminate foil pack with a desiccant bag.

Viral Clearance

The manufacturing procedure of TachoSil and its active substances Fibrinogen and Thrombin includes processing steps designed to reduce the risk of viral transmission. In particular, pasteurization, precipitation and adsorption steps are included in the manufacturing of Fibrinogen and Thrombin and pH treatment in the manufacturing of Collagen Sponge.

Validation studies for Fibrinogen and Thrombin and Collagen Sponge manufacturing steps were conducted for their capacity to inactivate and/or remove viruses. These in vitro validation studies were conducted, using samples from manufacturing intermediates spiked with virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The cumulative virus reduction factors (expressed as log10) are shown in Table 3 for each virus tested.

TachoSil is sterilized by gamma irradiation after completion of inner and outer packaging, resulting in a sterile product in a sterile inner package. A validation study was conducted evaluating the capacity of gamma irradiation to inactivate viruses. The virus reduction factors (expressed as log10) for the final sterilization of TachoSil by gamma irradiation are shown in Table 4 for each virus tested.

Table 3 Cumulative virus reduction factors for the components of TachoSil

Cumulative Reduction Factors for Virus Removal/Inactivation of Human Thrombin
* HIV-1:      Human Immunodeficiency Virus 1 HSV:        Herpes Simplex Virus BVDV:      Bovine Viral Diarrhoea Virus HAV:        Hepatitis A Virus PRV:        Pseudorabies Virus PI-3:        Parainfluenza Virus type 3 PPV:        Porcine Parvovirus Reo 3:      Reo Virus type 3 † Additional reduction factor [log10] of 1.6 for PRV not included in cumulative reduction factor for HSV
	Reduction Factors [log10] of Virus* tested
Manufacturing step	HIV-1	HSV	BVDV	CPV	HAV
Pasteurization, precipitation and adsorption steps	≥ 19.6	≥ 21.4	≥ 13.4	6.6	8.7
Cumulative Reduction Factors for Virus Removal/Inactivation of Human Fibrinogen
	Reduction Factors [log10] of Virus* tested
Manufacturing step	HIV-1	HSV†	BVDV	CPV	HAV
Pasteurization, precipitation and adsorption steps	≥9.6	≥ 9.1	≥ 11.2	4.4	≥ 6.7
Reduction Factors for Virus Removal/Inactivation of the Collagen Sponge (equine)
		Reduction Factors [log10] of Virus* tested
Manufacturing step		PRV	PI-3	PPV	Reo3
pH treatment		≥ 5.7	≥ 5.9	---	---

Table 4 Virus reduction factors for the final sterilization by gamma irradiation

Reduction Factor of Gamma Irradiation (Final Sterilization of TachoSil)
* PRV:        Pseudorabies Virus PI-3:        Parainfluenza Virus type 3 PPV:        Porcine Parvovirus Reo 3:      Reo Virus type 3
	Reduction Factors [log10] of Virus* tested
Manufacturing step	PRV	PI-3	PPV	Reo3
Gamma Irradiation	≥ 4.7	≥ 4.0	3.0	≥ 6.2

All infections considered by a physician possibly to have been transmitted by this product should be reported to Baxter. (See WARNINGS AND PRECAUTIONS, Transmissible Infectious Agents (5.6))

TachoSil Patch - Clinical Pharmacology

Mechanism of Action

TachoSil contains human fibrinogen and human thrombin as a dried coating on the surface of an equine collagen patch (Fig. 3A). When TachoSil is in contact with physiological fluids, the components of the coating dissolve and partly diffuse into the wound surface. Soluble fibrinogen is transformed into fibrin, by the enzymatic action of thrombin, which polymerizes into a fibrin clot that adheres the collagen patch to the wound surface and achieves hemostasis (Fig 3B). TachoSil exhibits flexibility to accommodate for the physiological movements of tissues and organs and can withstand pressures up to 61.4 hPa (46.1 mm Hg).

Figure 3: SEM (Scanning Electron Microscopy) photos of TachoSil

A. This side view of the TachoSil Patch shows the coating of the human plasma components anchored to the indentations of the collagen carrier.	B. The deposition of a fibrin clot formed from the fibrinogen and thrombin of the coating causes hemostasis and conglutination of the TachoSil Patch to the tissue wound.

In animal studies, TachoSil progressively biodegrades with only a few remnants left after 13 weeks. After complete biodegradation, no remnants of the TachoSil Patch remained in the body.

Pharmacodynamics

Clinical studies demonstrating hemostasis were conducted in a total of 119 patients undergoing cardiovascular surgery. Efficacy data is provided in section 14.

Pharmacokinetics

Pharmacokinetic studies have not been performed. Because TachoSil is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of TachoSil or studies to determine the genotoxicity or the effect of TachoSil on fertility have not been performed.

Clinical Studies

An open-label, multicenter, 1:1 randomized, parallel-group study comparing TachoSil with comparator (hemostatic fleece without additional active coagulation stimulating compounds) treatment was conducted to evaluate TachoSil for control of bleeding in 119 patients undergoing cardiovascular surgery requiring cardiopulmonary bypass procedure.

In the Intention to Treat (ITT) population (119 patients), 59 patients were treated with TachoSil and 60 patients were treated with the comparator. A larger proportion of patients in the TachoSil treatment group (44/59; 74.6%) than in the comparator treatment group (20/60; 33.3%) achieved hemostasis within 3 minutes, which was a statistically significant difference (p<0.0001, CMH test controlling for center). Fifty-six out of 59 (94.9%) patients in the TachoSil treatment group achieved hemostasis at 6 minutes compared to 43 out of 60 (71.7%) in the comparator treatment group, which was statistically significant (p=0.0006, CMH test controlling for center), see Table 5.

Table 5 Efficacy results in cardiovascular surgery, by treatment, ITT population (n = 119)

Treatment	Total number of patients who achieved hemostasis	Proportion of patients who achieved hemostasis	95% CI for proportion*	p-value†
* Normal approximation to the binominal distribution is used to construct the asymptotic confidence intervals † Cochran-Mantel-Haenszel test controlling for center ‡ Hemostatic fleece material without additional active coagulation stimulating compounds
Hemostasis at 3 min
TachoSil (n =59)	44	0.746	[0.635; 0.857]	< 0.0001
Comparator‡ (n=60)	20	0.333	[0.214; 0.453]
Hemostasis at 6 min
TachoSil (n =59)	56	0.949	[0.893;1.000]	< 0.0006
Comparator‡(n=60)	43	0.717	[0.603; 0.831]

How Supplied/Storage and Handling

Each patch is packaged in an appropriately sized blister pack of polystyrene formed foil and grid varnish coated medicinal paper and overwrapped with an aluminum laminate foil pack with a desiccant bag. Each patch is packaged individually.

TachoSil is supplied in the following pack sizes:

• Package with 1 patch of 9.5 cm × 4.8 cm          (NDC 0944-8701-01)


• Package with 2 patches of 4.8 cm × 4.8 cm       (NDC 0944-8702-02)


• Package with 1 patch of 3.0 cm × 2.5 cm          (NDC 0944-8703-01)


• Package with 5 patches of 3.0 cm × 2.5 cm       (NDC 0944-8703-05)

Storage

TachoSil should be stored between 2ºC and 25ºC.

TachoSil does not require refrigeration. Do not freeze.

Patient Counseling Information

Advise patients that, because TachoSil is made from human blood, it may carry a risk of transmitting infections agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent (See WARNINGS AND PRECAUTIONS, Transmissible Infectious Agents (5.6) and DESCRIPTION (11)).

Instruct patients to consult their physician if symptoms of B19 virus infection appear (fever, drowsiness, chills and runny nose followed about two weeks later by a rash and joint pain (see USE IN SPECIFIC POPULATIONS, Pregnancy (8.1)).

Distributed by:

Baxter Healthcare Corporation

Westlake Village, CA 91632 USA

Manufactured by:

Nycomed Austria GmbH

St. Peter Strasse 25

A-4020 Linz

Austria

U.S. License No. 1825

Issued April 5, 2010
1US Trademark

Registration No. 2,951,400

1

TachoSil is a registered trademark of Nycomed Pharma AS.

PRINCIPAL DISPLAY PANEL - 9.5 cm Patch Carton

NDC 0944-8701-01

Absorbable Fibrin

Sealant Patch

TachoSil®

1 patch of 9.5 cm × 4.8 cm

Single use only

Topical use only

Do not use intravascularly

Store at 2°C to 25°C (36°F to 77°F)

Do not freeze

Directions for use: See package insert

Use immediately once the foil pouch is opened

Do not resterilize

Dispose of any unused product or waste material

in accordance with local requirements

Rx Only

Product Code 1144922

Baxter

PRINCIPAL DISPLAY PANEL - 4.8 cm Patch Carton

NDC 0944-8702-02

Absorbable Fibrin

Sealant Patch

TachoSil®

2 patches of 4.8 cm × 4.8 cm

Single use only

Topical use only

Do not use intravascularly

Store at 2°C to 25°C (36°F to 77°F)

Do not freeze

Directions for use: See package insert

Use immediately once the foil pouch is opened

Do not resterilize

Dispose of any unused product or waste material

in accordance with local requirements

Rx Only

Product Code 1144923

Baxter

PRINCIPAL DISPLAY PANEL - 3.0 cm Patch Carton

NDC 0944-8703-01

Absorbable Fibrin

Sealant Patch

TachoSil®

1 patch of 3.0 cm × 2.5 cm

Single use only

Topical use only

Do not use intravascularly

Store at 2°C to 25°C (36°F to 77°F)

Do not freeze

Directions for use: See package insert

Use immediately once the foil pouch is opened

Do not resterilize

Dispose of any unused product or waste material

in accordance with local requirements

Rx Only

Product Code 0000000

Baxter

TACHOSIL  thrombin human and fibrinogen  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0944-8701 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THROMBIN HUMAN (THROMBIN HUMAN) THROMBIN HUMAN 5.5 mg FIBRINOGEN (FIBRINOGEN) FIBRINOGEN 2.0 [USP'U]

Inactive Ingredients Ingredient Name Strength EQUUS CABALLUS COLLAGEN   ALBUMIN (HUMAN)   RIBOFLAVIN   SODIUM CHLORIDE   SODIUM CITRATE   ARGININE HYDROCHLORIDE

Product Characteristics Color YELLOW (active side) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0944-8701-01 1 POUCH In 1 CARTON contains a POUCH 1 1 BLISTER PACK In 1 POUCH This package is contained within the CARTON (0944-8701-01) and contains a BLISTER PACK 1 1 PATCH In 1 BLISTER PACK This package is contained within a POUCH and a CARTON (0944-8701-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA125351	08/09/2010

TACHOSIL  thrombin human and fibrinogen  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0944-8702 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THROMBIN HUMAN (THROMBIN HUMAN) THROMBIN HUMAN 5.5 mg FIBRINOGEN (FIBRINOGEN) FIBRINOGEN 2.0 [USP'U]

Inactive Ingredients Ingredient Name Strength EQUUS CABALLUS COLLAGEN   ALBUMIN (HUMAN)   RIBOFLAVIN   SODIUM CHLORIDE   SODIUM CITRATE   ARGININE HYDROCHLORIDE

Product Characteristics Color YELLOW (active side) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0944-8702-02 2 POUCH In 1 C