Generic Name: Von Willebrand Factor/coagulation factor viii complex (human)
Dosage Form: powder for solution, for intravenous use

FULL PRESCRIBING INFORMATION

Indications and Usage for Von Willebrand Factor

Wilate is a Von Willebrand Factor/Coagulation Factor VIII Complex (Human) indicated for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

Clinical trials to evaluate the safety and efficacy of prophylactic dosing with Wilate to prevent spontaneous bleeding have not been conducted in VWD subjects.

Wilate is not indicated for the prevention of excessive bleeding during and after surgery in VWD patients.

Wilate is not indicated for Hemophilia A.

Von Willebrand Factor Dosage and Administration

• For Intravenous Use after Reconstitution
• Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders.
• Each vial of Wilate contains the labeled amount in International Units (IU) of Von Willebrand Factor (VWF) activity as measured with the Ristocetin cofactor assay (VWF:RCo), and coagulation factor VIII (FVIII) activity measured with the chromogenic substrate assay.
• The number of units of VWF:RCo and FVIII activities administered is expressed in IU, which are related to the current WHO standards for VWF and FVIII products. VWF:RCo and FVIII activities in plasma are expressed either as a percentage (relative to normal human plasma) or in IU (relative to the International Standards for VWF:RCo and FVIII activities in plasma).

Dosage in von Willebrand Disease

The ratio between VWF:RCo and FVIII activities in Wilate is approximately 1:1.

The dosage should be adjusted according to the extent and location of the bleeding. In VWD type 3 patients, especially in those with gastro-intestinal (GI) bleedings, higher doses may be required.

Dosing Schedule

Physician supervision of the treatment regimen is required. A guide for dosing in the treatment of major and minor hemorrhages is provided in Table 1.

The careful control of replacement therapy is especially important in life-threatening hemorrhages. When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII activity.[1 ]

Table 1Guide to Wilate Dosing for Treatment of Minor and Major Hemorrhages

*This may need to be continued for up to 3 days for minor hemorrhages and 5-7 days for major hemorrhages

Repeat doses are administered for as long as needed based upon repeat monitoring of appropriate clinical and laboratory measures.

Although dose can be estimated by the guidelines above, it is highly recommended that whenever possible, appropriate laboratory tests should be performed on the patient’s plasma at suitable intervals to assure that adequate VWF:RCo and FVIII activity levels have been reached and are maintained.

In the unlikely event that a patient who is actively bleeding should miss a dose, it may be appropriate to adopt a dosage depending on the level of coagulation factors measured, extent of the bleeding, and patient’s clinical condition.

Administration

Wilate is administered via intravenous infusion. Wilate is provided with a Mix2VialTM transfer device for reconstitution of the freeze-dried powder in diluent, a 10-mL syringe, an infusion set and two alcohol swabs.

Instructions for Reconstitution

	1) Warm the Powder and Diluent in the closed vials up to room temperature. This temperature should be maintained during reconstitution. If a water bath is used for warming, care must be taken to avoid water coming into contact with the rubber stoppers (latex-free) or the caps of the vials. The temperature of the water bath should not exceed +37°C (98°F). 2) Remove the caps from the concentrate (Wilate) vial and the diluent vial and clean the rubber stoppers with an alcohol swab.
	3) Peel away the lid of the outer package of the Mix2Vial™ transfer set. To maintain sterility, leave the Mix2Vial™ device in the clear outer packaging. Place the diluent vial on a level surface and hold the vial firmly. Take the Mix2Vial™ in its outer package and invert it over the diluent vial. Push the blue plastic cannula of the Mix2Vial™ firmly through the rubber stopper of the diluent vial (Fig. 1). While holding onto the diluent vial, carefully remove the outer package from the Mix2Vial™, being careful to leave the Mix2Vial™ attached firmly to the diluent vial (Fig. 2).
	4) With the concentrate (Wilate) vial held firmly on a level surface, quickly invert the diluent vial with the Mix2Vial™ attached and push the transparent plastic cannula end of the Mix2Vial™ firmly through the stopper of the concentrate (Wilate) vial (Fig. 3). The diluent will be drawn into the concentrate (Wilate) vial by the vacuum.
	5) With both vials still attached, gently swirl the product vial to ensure the product is fully dissolved to a clear solution. Once the contents of the Wilate vial are completely dissolved, firmly hold both the transparent and blue parts of the Mix2Vial™. Unscrew the Mix2Vial™ into two separate pieces (Fig. 4) and discard the empty diluent vial and the blue part of the Mix2Vial™.

• The powder should be reconstituted only directly before injection. As Wilate contains no preservatives, the solution should be used immediately after reconstitution.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• The solution is clear to slightly opalescent. If the concentrate fails to dissolve completely or an aggregate is formed, the preparation must not be used.

Instructions for Injection

1. With the Wilate vial still upright, attach a plastic disposable syringe to the Mix2Vial™ (transparent plastic part). Invert the system and draw the reconstituted Wilate into the syringe.
2. Once Wilate has been transferred into the syringe, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and detach the Mix2Vial™ from the syringe. Discard the Mix2Vial™ (transparent plastic part) and empty Wilate vial.
3. Clean the intended injection site with an alcohol swab.
4. Attach a suitable infusion needle to the syringe.
5. Inject the solution intravenously at a slow speed of 2-4 mL/minute.

• As a precautionary measure, the patient’s pulse rate should be measured before and during the injection. If a marked increase in the pulse rate occurs, the injection speed must be reduced or the administration must be interrupted.
• Any unused product or waste material should be disposed of in accordance with local requirements.

Incompatibilities

Wilate must not be mixed with other medicinal products or administered simultaneously with other intravenous preparation in the same infusion set.

Dosage Forms and Strengths

Wilate is a sterile, lyophilized powder for reconstitution for intravenous injection, provided in the following nominal strengths per vial:

• 450 IU VWF:RCo and 450 IU FVIII activities in 5-mL
• 900 IU VWF:RCo and 900 IU FVIII activities in 10-mL

Contraindications

Wilate is contraindicated for patients who have known anaphylactic or severe systemic reaction to plasma-derived products, any ingredient in the formulation, or components of the container. For a complete listing of ingredients, see Description (11).

Warnings and Precautions

Hypersensitivity

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed upon use of Wilate, and may in some cases progress to severe anaphylaxis (including shock) with or without fever.[2 ] Closely monitor patients receiving Wilate and carefully observe for any symptoms throughout the infusion period.

Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic symptoms occur, discontinue the administration immediately and contact the physician. Since inhibitor antibodies may occur concomitantly with anaphylactic reactions, patients experiencing an anaphylactic reaction should also be evaluated for the presence of inhibitors.[ 2]

Thromboembolic Risk

When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII activity.[1 ] Monitor plasma levels of VWF:RCo and FVIII activities in patients receiving Wilate to avoid sustained excessive VWF and FVIII activity levels, which may increase the risk of thrombotic events.

Inhibitor Formation

Patients with VWD, especially type 3 patients, may potentially develop neutralizing antibodies (inhibitors) to VWF. If a patient develops inhibitor to VWF (or FVIII), the condition will manifest itself as an inadequate clinical response. Thus, if the expected VWF activity plasma levels are not attained, or if bleeding is not controlled with an adequate dose or repeated dosing, perform an appropriate assay to determine if a VWF inhibitor is present. In patients with antibodies against VWF, VWF is not effective and infusion of this protein may lead to severe adverse events. Consider other therapeutic options for such patients. Physicians with experience in the care of patients with hemostatic disorders should direct their management.[3 ] In all such cases, it is recommended that a center specialized in bleeding disorders be contacted.

Since inhibitor antibodies may occur concomitantly with anaphylactic reactions, patients experiencing an anaphylactic reaction should also be evaluated for the presence of inhibitors.[2 ]

Infection Risk from Human Plasma

Wilate is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the variant Creutzfeldt-Jakob disease (vCJD) agent. There is also the possibility that unknown infectious agents may be present in such products. The risk that such products will transmit viruses has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses during manufacture. Despite these measures, such products may still potentially transmit disease. [4 ]

Record the batch number of the product every time Wilate is administered to a patient, and consider appropriate vaccination (against hepatitis A and B virus) of patients in regular/repeated receipt of Wilate. 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 Octapharma USA, Inc., telephone # 1-866-766-4860.

Monitoring and Laboratory Tests

Monitor plasma levels of VWF:RCo and FVIII activities in patients receiving Wilate to avoid sustained excessive VWF and FVIII activity levels, which may increase the risk of thrombotic events, particularly in patients with known clinical or laboratory risk factors.

Monitor for development of VWF and FVIII inhibitors. Perform assays to determine if VWF and/or FVIII inhibitor(s) is present if bleeding is not controlled with the expected dose of Wilate. [5 ]

Adverse Reactions

The most common adverse reactions to treatment with Wilate in patients with VWD have been urticaria and dizziness.

The most serious adverse reactions to treatment with Wilate in patients with VWD have been hypersensitivity 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 trails of another drug and may not reflect the rates observed in clinical practice.

There were 92 VWD patients who received Wilate on 5676 occasions including clinical studies that involved prophylactic use, treatment on demand, surgery, and pharmacokinetics. Their safety data showed that the most common adverse reactions were urticaria and dizziness (each with 2 patients; 2.2%). There were also four patients (4.4%) who showed seroconversion for antibodies to parvovirus B19 not accompanied by clinical signs of disease. Seroconversion has not been reported since implementation of minipool testing of plasma used for the manufacture of Wilate.

Post-Marketing Experience

The following adverse reactions have been identified during the post approval use of Wilate. 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 product exposure.

Post-marketing adverse reactions reported in patients treated for VWD include hypersensitivity reactions, dyspnea, nausea, vomiting, and cough.

Drug Interactions

No interactions with other medicinal products are known.

USE IN SPECIFIC POPULATIONS

Pregnancy

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

Labor and Delivery

Wilate has not been studied in labor or delivery. It should be administered to VWF-deficient women at labor or delivery only if clearly indicated. [6 ]

Nursing Mothers

Wilate has not been studied in lactating women.

Pediatric Use

Eleven pediatric patients with VWD between 5 to 16 years of age (8 type 3, 1 type 2, 2 type 1) were treated with Wilate for 234 bleeding episodes (BEs) in clinical studies. These studies showed that 88% of the BEs were treated successfully in this population (Table 7). No dose adjustment is needed for pediatric patients as administered dosages were similar to those used in the adult population (Table 8).

Geriatric Use

Although some of the patients who participated in the Wilate studies were over 65 years of age, the number of patients was inadequate to allow subgroup analysis to support recommendations in the geriatric population.

Von Willebrand Factor Description

Wilate is a human plasma-derived, sterile, purified, double virus inactivated Von Willebrand Factor/Coagulation Factor VIII Complex (Human). Wilate is supplied as a lyophilized powder for reconstitution for intravenous injection.

Wilate is labeled with the actual VWF:RCo and FVIII activities in IU per vial. The VWF activity (VWF:RCo) is determined using a manual agglutination method referenced to the current “WHO International Standard for Von Willebrand Factor Concentrate”. The FVIII activity is determined using a chromogenic substrate assay referenced to the current “WHO International Standard for Human Coagulation Factor VIII Concentrate”. The assay methodologies are according to European Pharmacopoeia (Ph.Eur.).

Wilate contains no preservative. The diluent for reconstitution of the lyophilized powder is Water for Injection with 0.1% Polysorbate 80.

No albumin is added as a stabilizer. The resulting specific activity of Wilate is ( 60 IU VWF:RCo and ( 60 IU FVIII activities per mg of total protein.

The nominal composition of Wilate is as follows:

Wilate is derived from large pools of human plasma collected in U.S. FDA approved plasma donation centers. All plasma donations are tested for viral markers in compliance with requirements of EU CPMP and FDA guidances. In addition, the limit for the titer of human parvovirus B19 DNA in the manufacturing pool is set not to exceed 104 IU/mL.

The product is manufactured from cryoprecipitate, which is reconstituted in a buffer and treated with aluminum hydroxide followed by two different chromatography steps, ultra- and diafiltration, and sterile filtration. The manufacturing process includes two virus inactivation steps, namely, treatment with an organic solvent/detergent (S/D) mixture, composed of tri-n-butyl phosphate (TNBP) and Octoxynol-9, and a terminal dry heat (TDH) treatment of the lyophilized product in final container [at +100°C (212°F) for 120 minutes at a specified residual moisture level of 0.7 – 1.6%]. In addition, the ion-exchange chromatography step utilized during Wilate manufacturing also removes some viruses [7 ]. The mean cumulative virus reduction factors of these steps are summarized in Table 2.

Table 2Virus Reduction During Wilate Manufacturing

na: not applicable

nd: not done (S/D reagents present)

HIV-1: Human Immunodeficiency Virus – 1

SBV: Sindbis Virus

BVDV: Bovine Viral Diarrhea Virus

PRV: Pseudorabies Virus

REO 3: Reovirus Type 3

HAV: Hepatitis A Virus

PPV: Porcine Parvovirus

Von Willebrand Factor – Clinical Pharmacology

Mechanism of Action

VWF and FVIII are normal constituents of human plasma. VWF is a multimeric protein with two key functions. It is an adhesive molecule, which mediates the binding between platelets and damaged sub-endothelial tissues. It is also a carrier protein, involved in the transport and stabilization of FVIII. Patients suffering from VWD have a deficiency or abnormality of VWF. This reduction in VWF concentration in the bloodstream result in a correspondingly low FVIII activity and an abnormal platelet function thereby resulting in excessive bleeding. [8 ]

The VWF in Wilate is derived from normal human plasma and is expected to behave in the same way as endogenous VWF. Thus, administration of VWF allows correction of the hemostatic abnormalities in VWD patients at two levels:

• The VWF re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds both to the vascular sub-endothelium and to the platelet membrane), providing primary hemostasis, as shown by the shortening of the bleeding time. This effect occurs immediately.
• The VWF induces correction of the associated FVIII deficiency in VWD. Administered intravenously, VWF binds endogenous FVIII (which is produced normally by the patient), and by stabilizing this factor, avoids its rapid degradation. This action is slightly delayed. However, administration of a FVIII-containing VWF preparation like Wilate rapidly restores the FVIII activity level to normal.[8]

Pharmacodynamics

There have been no specific pharmacodynamic studies on Wilate.

Pharmacokinetics

An open label, prospective, randomized, controlled, two-arm cross-over Phase 2 study with Wilate and a comparator product was conducted at 6 sites in the US. In this study, pharmacokinetic (PK) profiles of Wilate were determined by FVIII activity, VWF:RCo, VWF:Ag, and VWF:CB.

Each of twenty-two subjects with inherited VWD [Type 1, n=6; Type 2, n=9 (6 Type 2A, 1 Type 2B, and 2 Type 2M); and Type 3, n=7] received an intravenous bolus dose of Wilate containing approximately 40 IU of VWF:RCo/kg BW. Twenty subjects completed the study as per protocol. PK parameters of VWF:RCo and FVIII are summarized in Table 3 and Table 4, respectively.

Table 3Pharmacokinetic Parameters of VWF:RCo:mean ± SD (range)

Cmax = peak concentration; AUC = area under curve; CL = clearance; Vss = volume of distribution at steady state; MRT = mean residence time

The PK parameters reported in Table 3 are based on VWF:RCo values obtained using a modified Behring Coagulation System (BCS) analytical method. The modified BCS was used because of its validated lower variability compared to the standard BCS. The measured concentrations (IU VWF:RCo/mL) are higher by the modified BCS than by the standard BCS analytical method which is used in some clinical laboratories. Dose adjusted Cmax and AUC determined by this modified BCS method are approximately 1.5 times higher than those by the standard BCS method. No difference has been found in incremental recovery.

Table 4Pharmacokinetic Parameters of FVIII:C: mean ± SD (range) – chromogenic

Cmax = peak concentration; AUC = area under curve; CL = clearance; Vss = volume of distribution at steady state; MRT = mean residence time

Effect of age and VWD type on the pharmacokinetics of Wilate:

Due to small sample size (in age or VWD type subsets) and high PK variability, it is difficult to conclude if age or type of VWD had any impact on the pharmacokinetics of Wilate.

Effect of gender on the pharmacokinetics of Wilate:

Based on PK data of Wilate from 8 males and 12 females, it appears that the females (4.35 ± 1.54 mL/hr/kg) had higher clearance of VWF:RCo than the males (3.16 ± 1.19 mL/hr/kg). The clinical significance of this finding is not known.

Clinical Studies

Clinical efficacy of Wilate in the control of bleeding in patients with VWD was determined in four prospective clinical studies. This included treatment of 1068 bleeding episodes (BEs). Data were obtained from 70 VWD patients, of which 37 were type 3. BEs are summarized in Table 5. The treated BEs were analyzed for efficacy using a set of objective criteria in addition to a subjective 4-point hemostatic efficacy scale (excellent, good, moderate and none). In assessing the efficacy using these objective criteria, the treatment of a bleeding episode was classified as a success only if none of the criteria listed below was fulfilled:

• the episode was additionally treated with another VWF-containing product (excluding whole blood),
• the patient received a blood transfusion during the episode,
• follow-up treatment with a daily dosage of Wilate that was equal or more than 50% (≥ 50%) above the initial dose (for bleeding episodes with more than 1 day of treatment),
• treatment duration of more than 4 days (> 4 days) in cases of severe bleeding (other than gastrointestinal),
• treatment duration of more than 3 days (> 3 days) in cases of moderate bleeding (other than gastrointestinal),
• treatment duration of more than 2 days (> 2 days) in cases of minor bleeding (other than gastrointestinal),
• the last efficacy rating of the bleeding episode was ‘moderate’ or ‘none’.

Among the 70 VWD patients administered Wilate in clinical studies (excluding the PK study), 45 of them received on demand treatment for BEs. Using the above objective criteria, corresponding efficacy for each bleeding event was rated as being successful in 84% of the episodes. In these 45 patients with BEs, 93% of the successfully treated BEs occurred in VWD type 3 patients (n=25).

Table 5Proportion of successful treatments of bleeding episodes with Wilate (n=45)

The dosing information for the 972 successfully treated “bleeding episodes” (1423 infusions) for regional bleeding is summarized in Table 6. For the purpose of assigning success/failure to regional bleeding that occurred at the same time, the bleeding at different sites over the same time span would be counted as separate BEs. Thus, the number of these “episodes” would be different from that in the overall evaluation for success/failure of Wilate in the treatment of bleeding episodes in Table 5.

Table 6Administered dosages (VWF:RCo in IU/kg) in bleeding episodes* successfully treated with Wilate: Mean + SD (Range) (n=45)

**“Other” Includes mostly muscle bleeds, hematuria, ecchymosis, hematoma and other miscellaneous sites of bleeding

The majority of BEs were treated for 1-3 days. In patients with GI bleeds, the duration for product use to control bleeding could be much longer (up to 7 days).

For pediatric patients (≤16 yrs), a summary of the number of BEs treated and corresponding objective efficacy ratings are provided in Table 7.

Table 7Efficacy in bleeding episodes in pediatric population (5 to 16 yrs) (n=11) – Proportion of successful treatments of bleeding episodes with Wilate

The dosing information for the 211 successfully treated bleeding episodes (289 infusions) is summarized in Table 8. Multiple bleeding sites are counted as separate episodes.

Table 8Administered dosages (VWF:RCo in IU/kg) in bleeding episodes* successfully treated with Wilate in pediatric population (5 to 16 yrs) (n=11): Mean + SD (Range)

**“Other” Includes mostly muscle bleeds, hematuria, ecchymosis, hematoma and other miscellaneous sites of bleeding

REFERENCES

1. Mannucci P.M.: Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002;88:378-379
2. Mollison.P.L., Engelfriet C.P., Contreras M.: Some unfavourable effects of transfusion; in Klein H.G., Anstee D.J. (eds): Mollison’s Blood Transfusion in Clinical Medicine. Blackwell Publishing, 2005, pp 666-700
3. Mannucci P.M., Federici A.B.: Antibodies to Von Willebrand Factor in von Willebrand disease; in Aledort L.M. (ed): Inhibitors to Coagulation Factors. New York, Plenum Press, 1995, pp 87-92
4. Y. Kasper, C.K., Kipnis, S.A. Hepatitis and Clotting Factor Concentrates. JAMA1972; 221:510
5. X. Biggs, R. Jaundice and Antibodies Directed Against Factors VIII and IX in Patients Treated for Haemophilia or Christmas Disease in the United Kingdom. Br J Haematol 1974; 26:313-329
6. Azzi A., Morfini M., Mannucci P.M.: The transfusion-associated transmission of parvovirus B19. Transfus.Med.Rev. 1999;13:194-204
7. Stadler M., et al. Characterisation of a novel high-purity, double virus inactivated Von Willebrand Factor and Factor VIII concentrate (Wilate). DOI: 10.1016/j.biologicals. Biologicals 2006, 34:281-288 1-8.
8. Mannucci P.M.: Treatment of von Willebrand’s disease. New England Journal of Medicine 2004;351:683-694

How Supplied/Storage and Handling

• Wilate is supplied in a package with a single-dose vial of powder and a vial of diluent (Water for Injection with 0.1% Polysorbate 80), together with a Mix2VialTM transfer device, a 10-mL syringe, an infusion set and two alcohol swabs.
• Each vial of Wilate contains the labeled amount of IU of VWF:RCo activity as measured using a manual agglutination method, and IU of FVIII activity measured with a chromogenic substrate assay.
• Components used in the packaging of Wilate contain no latex.

Shelf life

• Store Wilate for up to 36 months at +2°C to +8°C (36°F to 46°F) protected from light from the date of manufacture. Within this period, Wilate may be stored for a period of up to 6 months at room temperature (maximum of +25°C or 77°F). The starting date of room temperature storage should be clearly recorded on the product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earliest. Do not freeze.
• Do not use after the expiration date.
• Store in the original container to protect from light.
• Reconstituted the Wilate powder only directly before injection. Use the solution immediately after reconstitution. Use the reconstituted solution on one occasion only, and discard any remaining solution.

Patient Counseling Information

• Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic symptoms occur, patients should discontinue the administration immediately and contact their physician [see Warnings and Precautions (5.1)].
• Inform patients that undergoing multiple treatments with Wilate may increase the risk of thrombotic events thereby requiring frequent monitoring of plasma VWF:RCo and FVIII activities . [see Warnings and Precautions (5.2)].
• Inform patients that there is a potential of developing inhibitors to VWF, leading to an inadequate clinical response. Thus, if the expected VWF activity plasma levels are not attained, or if bleeding is not controlled with an adequate dose or repeated dosing, contact the treating physician.[2] [see Warnings and Precautions (5.3)].
• Inform patients that despite procedures for screening donors and plasma as well as those for inactivation or removal of infectious agents, the possibility of transmitting infective agents with plasma-derived products cannot be totally excluded [see Warnings and Precautions (5.4)].

Manufactured by:

Octapharma Pharmazeutika Produktionsges.m.b.H.

Oberlaaer Strasse 235

A-1100 Vienna, Austria

U.S. License No. 1646

Distributed by:

Octapharma USA Inc.

121 River Street, 12th floor

Hoboken, NJ 07030

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL

Von Willebrand Factor/Coagulation Factor VIII Complex (Human)

Octapharma Pharmazeutika Produktionsges.m.b.H

450IU/5mL

NDC 67467-181-01

900IU/10mL

NDC 67467-181-02

Revised: 01/2010Octapharma Pharmazeutika Produktionsgesellschaft m.b.H.

Generic Name: diphenidol
Dosage Form: Tablets

‘Vontrol’ may cause hallucinations, disorientation, or confusion. For this reason, its use is limited to patients who are hospitalized or under comparable, continuous, close, professional supervision. Even then, the physician should carefully weigh the benefits against the possible risks and give due consideration to alternate therapeutic measures.

Vontrol Description

Diphenidol, α, α-diphenyl-1-piperidinebutanol, is a compound not related to the antihistamines, phenothiazines, barbiturates, or other agents with antivertigo or antiemetic action. It has this configuration:

Each round, orange ‘Vontrol’ tablet is debossed SKF and 25 and contains diphenidol hydrochloride equivalent to diphenidol, 25 mg. Inactive ingredients consist of acacia, calcium sulfate, cellulose, FD&C Yellow No. 5 (tartrazine), FD&C Yellow No. 6, magnesium stearate and starch.

ACTIONS

‘Vontrol’ (diphenidol, SK&F) apparently exerts a specific antivertigo effect on the vestibular apparatus to control vertigo and inhibits the chemoreceptor trigger zone to control nausea and vomiting.

INDICATIONS (SEE WARNINGS)

1. VERTIGO—‘Vontrol’ is indicated in peripheral (labyrinthine) vertigo and associated nausea and vomiting, as seen in such conditions as: Meniere’s disease, middle- and inner-ear surgery (labyrinthitis).
2. NAUSEA AND VOMITING—‘Vontrol’ is indicated in the control of nausea and vomiting, as seen in such conditions as: postoperative states, malignant neoplasms and labyrinthine disturbances.

Contraindications

Known hypersensitivity to the drug is a contraindication. Anuria is a contraindication. (Since approximately 90% of the drug is excreted in the urine, renal shutdown could cause systemic accumulation.)

Warnings

‘Vontrol’ (diphenidol, SK&F) may cause hallucinations, disorientation or confusion. For this reason, its use is limited to patients who are hospitalized or under comparable, continuous, close, professional supervision. Even then, the physician should carefully weigh the benefits against the possible risks and give due consideration to alternate therapeutic measures.

The incidence of auditory and visual hallucinations, disorientation and confusion appears to be less than ½% or approximately one in 350 patients. The reaction has usually occurred within three days of starting the drug in recommended dosage and has subsided spontaneously usually within three days after discontinuation of the drug. Patients on ‘Vontrol’ should be observed closely and in the event of such a reaction the drug should be stopped.

Usage in Pregnancy

Use of any drug in pregnancy, lactation or in women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to the mother and child.

In animal teratogenesis and reproduction studies of ‘Vontrol’ (diphenidol, SK&F), there were no significant differences between drug-treated groups and untreated control groups, except as noted under animal Reproduction Studies (see “Pharmacology [animal],” column 4).

In 936 patients who received ‘Vontrol’ during pregnancy, the incidences of normal and abnormal birth were comparable to those reported in the literature for the average population of pregnant patients. And in no instance was there any evidence that ‘Vontrol’ played a part in birth abnormality (see “In Pregnancy,” column 5).

‘Vontrol’ is not indicated for use in nausea and vomiting of pregnancy, since the therapeutic value and safety in this indication have not yet been determined.

Precautions

The antiemetic action of ‘Vontrol’ (diphenidol, SK&F) may mask signs of overdose of drugs (e.g., digitalis) or may obscure diagnosis of conditions such as intestinal obstruction and brain tumor.

Although there have been no reports of blood dyscrasias with ‘Vontrol’, patients should be observed regularly for any idiosyncratic reactions.

‘Vontrol’ has a weak peripheral anticholinergic effect and should be used with care in patients with glaucoma, obstructive lesions of the gastrointestinal and genitourinary tracts, such as stenosing peptic ulcer, prostatic hypertrophy, pyloric and duodenal obstruction, and organic cardiospasm.

‘Vontrol’ Tablets contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Usage in Children

‘Vontrol’ is not recommended for use in children under 50 pounds. (See Dosage and Administration—Children.)

Adverse Reactions

Auditory and visual hallucinations, disorientation and confusion have been reported. Drowsiness, overstimulation, depression, sleep disturbance, dry mouth, g.i. irritation (nausea and indigestion), or blurred vision may occur.

Rarely, slight dizziness, skin rash, malaise, headache, or heartburn may occur. Mild jaundice of questionable relationship to the use of ‘Vontrol’ (diphenidol, SK&F) has been reported. Slight, transient lowering of blood pressure has been reported in a few patients.

(See laboratory studies under “Pharmacology [human],” Column 4.)

DOSAGE AND ADMINISTRATION (SEE WARNINGS)

ADULTS—FOR VERTIGO OR NAUSEA AND VOMITING

The usual dose is one tablet (25 mg) every four hours as needed. Some patients may require two tablets (50 mg).

CHILDREN—FOR NAUSEA AND VOMITING

These recommendations are for nausea and vomiting only. There has been no experience with ‘Vontrol’ in vertigo in children.

Unit doses in children are best calculated by body weight: usually 0.4 mg./lb.

Children’s doses usually should not be given more often than every four hours. However, if symptoms persist after the first dose, administration may be repeated after one hour. Thereafter, doses may be given every four hours as needed.

The total dose in 24 hours should not exceed 2.5 mg./lb.

NOTE: The drug is not recommended for use in children under 50 pounds. The dosage for children 50 to 100 pounds is one tablet (25 mg.).

Overdosage

In the event of overdosage, the patient should be managed according to his symptoms. Treatment is essentially supportive, with maintenance of blood pressure and respiration, plus careful observation. Early gastric lavage may be indicated depending on the amount of overdose and nature of symptoms.

How is Vontrol Supplied

Tablets containing 25 mg. diphenidol, as the hydrochloride, in bottles of 100.

PHARMACOLOGY (ANIMAL)

‘Vontrol’ (diphenidol, SK&F) exerts its antiemetic effect primarily by inhibiting the chemoreceptor trigger zone, as evidenced by its activity in blocking emesis induced by apomorphine in dogs. In this regard ‘Vontrol’, as the hydrochloride salt, has a potency equal to the potent phenothiazine antiemetic, chlorpromazine hydrochloride. In animals ‘Vontrol’ has only weak parasympatholytic activity and no significant sedative, tranquilizing or antihistaminic action or effects on blood pressure, heart rate, respiration or the electrocardiogram.

Subacute and chronic toxicity studies in rats and dogs, in which large doses of ‘Vontrol’, as the hydrochloride salt, were administered orally and intramuscularly for periods up to one year, revealed no significant effects on hematology, liver function, kidney function or blood glucose determinations. Histological examination of the animals’ tissues did not reveal any significant lesions attributable to administration of ‘Vontrol’.

Reproduction Studies

Teratogenesis and reproduction studies were carried out in rats and rabbits. In rats, ‘Vontrol’ (diphenidol, SK&F), as the hydrochloride salt, was fed daily to male and female animals in doses of 20 mg./kg. and 40 mg./kg. (approximately three and six times the maximum recommended daily dose in adult humans) for 60 days before mating, and during mating, gestation and lactation for each of two litters. There were no significant differences between drug-treated and untreated control groups with regard to conception rate, litter size, live birth or viability in either of the two litters. There was no congenital anomaly among the offspring. In rabbits, ‘Vontrol’, as the hydrochloride salt, was fed in the diets in doses of 5 mg./kg. or 75 mg./kg. (approximately equal to, and 12 times as much as, the maximum recommended daily dose in adult humans) from the first day of gestation through the 26th or 27th day of gestation, when the young were delivered by Cesarean section. There were no significant differences between drug-treated and control groups with regard to number and weight of fetuses, numbers of resorption sites or viable fetuses. There was also no statistically significant difference between drug-treated and control groups with regard to the total percentage of underdeveloped fetuses. However, when data were calculated on the basis of a ratio between underdeveloped fetuses and number of pregnant does, an adverse dose-related effect was observed in the high-dose test group.

PHARMACOLOGY (HUMAN)

Three double-blind controlled studies comparing ‘Vontrol’ (diphenidol, SK&F) to placebo were carried out: one in 32 male volunteers over a four-week period; one in 45 volunteers of whom 15 were studied for 12 weeks and 17 for 24 weeks; and one in 48 volunteers of whom 36 were studied for 12 weeks.

In the first study ‘Vontrol’, as the hydrochloride salt, was given orally in daily doses that were started at 75 mg. during the first week and graduated up to 200 mg. by the fourth week. In the second study, one group received ‘Vontrol’ orally, as the hydrochloride salt, titrated up to 500 mg. daily, then down to 200 mg. daily; another group received a maximum of 200 mg. daily. In the third study, patients received oral doses of 200 mg. to 300 mg. of ‘Vontrol’ daily, as the hydrochloride or pamoate salts.

The studies included these laboratory determinations: complete blood counts (including hemoglobin and hematocrit determinations), urinalyses (including microscopic examination), serum alkaline phosphatase, serum bilirubin, and bromsulphalein retention. The studies also included records of weight and blood pressure and, in one, electrocardiograms.

In two of these studies, clinical laboratory changes were seen among volunteers in both treated and control groups. The changes included: extrasystoles, white cells in the urine, increase in prothrombin time, rise in hematocrit, rise in leucocytes, rise in eosinophils, and rise or reduction in neutrophils. At no time in any study did changes in the treated group differ significantly from those in the control group.

‘Vontrol’, as the hydrochloride salt, was given orally to 17 children (aged five to 15). Total daily doses ranged from 90 to 240 mg. Complete blood counts and, in some patients, urinalyses were done before treatment and after approximately four days of treatment. There was no significant difference between pre- and post-treatment laboratory determinations in any child. No side effects were seen.

EXCRETION

Following oral administration of ‘Vontrol’ (diphenidol, SK&F) to dogs, as the hydrochloride or pamoate salts, and to humans, as the hydrochloride salt, peak blood concentration of the drug generally occurs in one and a half to three hours. In dogs and rats, virtually all of an oral dose of C14-labeled ‘Vontrol’ is excreted in the urine and feces within three to four days, as determined by radioactivity counts. Approximately the same percentage of an administered dose appeared in the urine of dogs following either oral administration of the hydrochloride salt or rectal administration of the free base.

IN PREGNANCY

Investigators kept follow-up records on 936 patients who had received ‘Vontrol’ (diphenidol, SK&F) at some time during pregnancy, primarily during the first trimester.

Of the 936 women, 864 (92%) had normal births of normal infants.

Seventy-two (8%) of the women experienced some birth abnormality. Of the 72, six patients had premature but otherwise normal infants, 40 patients aborted, 10 had stillbirths, and 16 had infants with miscellaneous defects. These included hernias, congenital heart defects, hydrocephalus, internal strabismus, anencephalus, enlarged thyroid, and hypospadia.

These incidences of abnormal birth are lower than those generally reported in the literature for the average population of pregnant patients. And in no instance was there any evidence that the administration of ‘Vontrol’ played a part in birth abnormality.

DATE OF ISSUANCE JUNE 1985

© SmithKline Beckman Corporation, 1980

Smith Kline &French Laboratories Division of SmithKline Beckman Corporation Philadelphia, Pa. 19101

VN:L15 Printed in U.S.A.

Revised: 06/2006SmithKline Beckman Corporation

Generic Name: diclofenac sodium
Dosage Form: extended release tablets

Voltaren®-XR
(diclofenac sodium extended-release) tablets, USP
Tablets of 100 mg
Rx only
Prescribing Information

DESCRIPTION

Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is a benzeneacetic acid derivative. Voltaren-XR is available as extended-release tablets of 100 mg (light pink) for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula

The inactive ingredients in Voltaren-XR include: cetyl alcohol, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, sucrose, talc, titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Voltaren-XR, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). When Voltaren-XR is taken with food, there is a delay of 1 to 2 hours in the Tmax and a two-fold increase in Cmax values. The extent of absorption of diclofenac, however, is not significantly affected by food intake.

Distribution

The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 μg/mL) achieved with recommended doses.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4′-hydroxy-, 5-hydroxy-, 3′-hydroxy-, 4′,5-dihydroxy- and 3′-hydroxy-4′-methoxy diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4′-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. However, diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion.

One diclofenac metabolite 4′-hydroxy- diclofenac has very weak pharmacologic activity.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.

Special Populations

Pediatric: The pharmacokinetics of Voltaren-XR has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Voltaren-XR elimination, so patients with hepatic disease may require reduced doses of Voltaren-XR compared to patients with normal hepatic function.

Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of Voltaren®-XR (diclofenac sodium extended-release) tablets, USP and other treatment options before deciding to use Voltaren-XR. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

      Voltaren-XR is indicated:

• For relief of the signs and symptoms of osteoarthritis
• For relief of the signs and symptoms of rheumatoid arthritis

CONTRAINDICATIONS

Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is contraindicated in patients with known hypersensitivity to diclofenac.

      Voltaren-XR should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).

      Voltaren-XR is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

      There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI Effects).

      Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Voltaren®-XR (diclofenac sodium extended-release) tablets, USP, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Voltaren-XR should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation

NSAIDs, including Voltaren-XR, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

      NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.

      To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Caution should be used when initiating treatment with Voltaren-XR in patients with considerable dehydration.

      Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of non-steroidal anti-inflammatory drug (NSAID) therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Voltaren-XR in patients with advanced renal disease. Therefore, treatment with Voltaren-XR is not recommended in these patients with advanced renal disease. If Voltaren-XR therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Hepatic Effects

Elevations of one or more liver tests may occur during therapy with Voltaren-XR. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

      In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

      In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

      Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

      If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Voltaren-XR should be discontinued immediately.

      To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

      To minimize the potential risk for an adverse liver related event in patients treated with  Voltaren-XR, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Voltaren-XR with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Voltaren-XR. Voltaren-XR should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma.) Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Voltaren-XR, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

Voltaren®-XR (diclofenac sodium extended-release) tablets, USP cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

      The pharmacological activity of Voltaren-XR in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Voltaren-XR. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Voltaren-XR, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

      NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Voltaren-XR who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Voltaren-XR should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Voltaren-XR, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. Voltaren-XR, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
3. Voltaren-XR, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy (see WARNINGS, Hepatic Effects).
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including Voltaren-XR, the CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Voltaren-XR should be discontinued.

Drug Interactions

Aspirin: When Voltaren-XR is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.

Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Cyclosporine: Voltaren-XR, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Voltaren-XR may increase cyclosporine’s nephrotoxicity. Caution should be used when Voltaren-XR is administered concomitantly with cyclosporine.

ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Furosemide: Clinical studies, as well as postmarketing observations, have shown that Voltaren-XR can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Voltaren-XR on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren-XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

ADVERSE REACTIONS

In patients taking Voltaren®-XR (diclofenac sodium extended-release) tablets, USP or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are:

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus.

Additional adverse experiences reported occasionally include:

Body as a Whole: fever, infection, sepsis

Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope

Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory System: asthma, dyspnea

Skin and Appendages: alopecia, photosensitivity, sweating increased

Special Senses: blurred vision

Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure.

Other adverse reactions, which occur rarely are:

Body as a Whole: anaphylactic reactions, appetite changes, death

Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

Digestive System: colitis, eructation, liver failure, pancreatitis

Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

Metabolic and Nutritional: hyperglycemia

Nervous System: convulsions, coma, hallucinations, meningitis

Respiratory System: respiratory depression, pneumonia

Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria

Special Senses: conjunctivitis, hearing impairment.

OVERDOSAGE

Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of Voltaren®-XR (diclofenac sodium extended-release) tablets, USP and other treatment options before deciding to use Voltaren-XR. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

      After observing the response to initial therapy with Voltaren-XR, the dose and frequency should be adjusted to suit an individual patient’s needs.

      For the relief of osteoarthritis, the recommended dosage is 100 mg q.d.

For the relief of rheumatoid arthritis, the recommended dosage is 100 mg q.d. In the rare patient where Voltaren-XR 100 mg/day is unsatisfactory, the dose may be increased to 100 mg b.i.d. if the benefits outweigh the clinical risks of increased side effects.

Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated tablets); Voltaren®-XR (diclofenac sodium extended-release) tablets, USP; Cataflam® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same.

HOW SUPPLIED

Voltaren®-XR (diclofenac sodium extended-release) tablets, USP

100 mg

Light pink, film-coated, round, biconvex with beveled edges (imprinted Voltaren XR on one side and 100 on the other side in black ink)

      Bottles of 100……………………………………………………..NDC 0078-0446-05

Do not store above 30ºC (86ºF). Protect from moisture.

Dispense in tight container (USP).

MEDICATION GUIDE FOR NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.

This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used: 

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pains
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name       Tradename

Celecoxib       Celebrex
Diclofenac       Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal       Dolobid
Etodolac       Lodine, Lodine XL
Fenoprofen       Nalfon, Nalfon 200
Flurbirofen       Ansaid
Ibuprofen       Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),       Combunox (combined with oxycodone)
Indomethacin       Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen       Oruvail
Ketorolac       Toradol
Mefenamic Acid       Ponstel
Meloxicam       Mobic
Nabumetone       Relafen
Naproxen       Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac       (copackaged with lansoprazole)
Oxaprozin       Daypro
Piroxicam       Feldene
Sulindac       Clinoril
Tolmetin       Tolectin, Tolectin DS, Tolectin 600

* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

The brands listed are the trademarks or register marks of their respective owners and are not all trademarks or register marks of Novartis.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

REV: MARCH 2009       .                                     T2009-40/T2009-31

Manufactured by:

Novartis Pharma Stein AG

Stein, Switzerland for

Novartis Pharmaceuticals Corporation

East Hanover, NJ 07936

©Novartis

PRINCIPAL DISPLAY PANEL

Package Label – XR 100 mg

Rx Only             NDC 0078-0446-05

Voltaren® (diclofenac sodium extended-release) tablets, USP

100 tablets

PHARMACIST: Dispense with Medication Guide attached or provided separeately.

Revised: 10/2009Novartis Pharmaceuticals Corporation