Von Willebrand Factor

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

Type of Hemorrhages	Loading Dosage (IU VWF:RCo /kg BW)	Maintenance Dosage (IU VWF:RCo /kg BW)	Therapeutic Goal
Minor Hemorrhages	20-40 IU/kg	20-30 IU/kg every 12-24 hours*	VWF:RCo and FVIII activity through levels of >30%
Major Hemorrhages	40-60 IU/kg	20-40 IU/kg every 12-24 hours*	VWF:RCo and FVIII activity through levels of >50%

*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 Mix2Vial TM 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 filtered solution is clear or slightly opalescent, colourless or slightly yellow. 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:

• 500 IU VWF:RCo and 500 IU FVIII activities in 5-mL


• 1000 IU VWF:RCo and 1000 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:

Component	Quantity/ 5 mL vial	Quantity/ 10 mL vial
VWF:RCo	500 IU	1000 IU
FVIII	500 IU	1000 IU
Total protein	≤ 7.5 mg	≤ 15.0 mg
Glycine	50 mg	100 mg
Sucrose	50 mg	100 mg
Sodium chloride	117 mg	234 mg
Sodium citrate	14.7 mg	29.4 mg
Calcium chloride	0.8 mg	1.5 mg
Water for injection	5 mL	10 mL
Polysorbate 80	1 mg/mL	1 mg/mL

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 10 4 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 2 Virus 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 3 Pharmacokinetic Parameters of VWF:RCo:mean ± SD (range)

Parameters	VWD type I (n = 5)	VWD type II (n = 9)	VWD type III (n = 6)	Total (n = 20)
Cmax (IU/dL)	74 ± 13 (62 - 91)	77 ± 18 (40 - 100)	79 ± 13 (65 - 102)	76 ± 15 (40 - 102)
AUC(0-inf) (IU*hr/dL)	1633 ± 979 (984 - 3363)	1172 ± 421 (571 - 1897)	995 ± 292 (527 - 1306)	1235 ± 637 (527 - 3363)
Half-life (hrs)	24.7 ± 17.9 (11.2 - 48.5 )	15.3 ± 6.3 (6.0 - 26.4)	9.1± 2.6 (5.7 - 12.9 )	15.8 ± 11.0 (5.7 - 48.5)
CL (mL/h/kg)	3.1 ± 1.1 (1.2 - 4.1)	4.1 ± 1.7 (2.0 - 7.1)	4.2 ± 1.4 (3.0 - 6.6)	3.9 ± 1.5 (1.2 - 7.1)
Vss (mL/kg)	81.7 ± 38.5 (15.3 - 74.2)	76.6 ± 35.4 (45.3 - 158.8)	49.4 ± 16.7 (29.7 - 67.1)	69.7 ± 33.2 (29.7 - 158.8)
MRT (hrs)	32.7 ± 25.8 (15.3 - 74.2)	19.7 ± 5.6 (9.9 - 27.1)	11.9 ± 2.9 (9.2 - 15.9)	20.6 ± 14.8 (9.2 - 74.2)
Recovery (%IU/kg)	1.8 ± 0.2 (1.5 - 2.0)	1.8 ± 0.5 (1.0 - 2.4)	2.1 ± 0.3 (1.8 - 2.6)	1.9 ± 0.4 (1.0 - 2.6)

C max = 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 C max 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 4 Pharmacokinetic Parameters of FVIII:C: mean ± SD (range) - chromogenic

Parameters	VWD type I (n = 5)	VWD type II (n = 8*)	VWD type III (n = 6)	Total (n = 19*)
Cmax (IU/dL)	117.1 ± 12.1 (103 - 135)	147.2 ± 32.6 (102 - 206)	120 ± 23 (91 - 148)	112 ± 23 (59 - 148)
AUC(0-inf) (IU*hr/dL)	1187 ± 382 (523 - 1483)	1778 ± 1430 (544 - 4821)	2670 ± 854 (1874 - 3655)	2290 ± 1045 (464 - 4424)
Half-life (hrs)	17.5 ± 4.9 (10.9 - 23.8)	23.6 ± 8.3 (12.6 - 34.7)	16.1 ± 3.1 (11.8 - 20.1)	19.6 ± 6.9 (10.9 - 34.7)
CL (mL/h/kg)	4.4 ± 3.7 (2.5 - 11.0)	2.5 ± 0.9 (1.2 - 3.5)	2.0 ± 0.6 (1.4 - 2.8)	2.9 ± 2.1 (1.2 - 11.0)
Vss (mL/kg)	95.0 ± 53.8 (57.1 - 190.0)	79.5 ± 23.1 (52.8 - 116.2)	44.2 ± 10.4 (31.8 - 57.1)	72.4 ± 36.2 (31.8 - 190.0)
MRT (hrs)	24.1 ± 5.5(17.2 - 31.5)	35.1 ± 14.2 (17.5 - 61.6)	23.0 ± 3.7 (18.0 - 27.7)	28.4 ± 11.1 (17.2 - 61.6)
Recovery (%IU/kg)	1.9 ± 0.5 (1.1 - 2.5)	2.2 ± 0.4 (1.6 - 2.8)	2.5 ± 0.5 (2.0 - 3.0)	2.2 ± 0.5 (1.1 - 3.0)

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

			95% CI
Episodes*	Successful	% Successes	Lower CL	Upper CL
1068	898	84.1	81.8	86.2

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

Location	All Doses considered		Initial Dose		Subsequent Doses
	# of infusions	Dose: Mean ± SD (Range)	# of infusions	Dose: Mean ± SD (Range)	# of infusions	Dose: Mean ± SD (Range)
Joints	801	26 ± 12 (7 - 69)	542	28 ± 13 (7 - 69)	259	21 ± 10 (7 - 60)
Epistaxis	132	24 ± 11 (8 - 78)	91	25 ± 10 (13 - 78)	41	22 ± 14 (8 - 77)
GI Tract	125	40 ± 20 (9 - 76)	64	43 ± 19 (9 - 76)	61	36 ± 21 (9 - 76)
Oral	41	26 ± 14 (8 - 80)	33	27 ± 14 (10 - 80)	8	24 ± 18 (8 - 60)
Gynecologic	87	27 ± 14 (9 - 77)	52	28 ± 17 (12 - 77)	35	26 ± 9 (9 - 52)
Other**	237	23 ± 12 (10 - 95)	189	24 ± 12 (12 - 95)	48	20 ± 13 (10 - 95)

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

			95% CI
Episodes*	Successful	% Successes	Lower CL	Upper CL
234	205	87.6	82.7	91.5

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 8 Administered 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)

Location	All Doses considered		Initial Dose		Subsequent Doses
	# of infusions	Dose: Mean ± SD (Range)	# of infusions	Dose: Mean ± SD (Range)	# of infusions	Dose: Mean ± SD (Range)
Joints	158	30 ± 13 (12 - 69)	117	32 ± 13 (14 - 69)	41	25 ± 9 (12 - 62)
Epistaxis	30	27 ± 14 (12 - 77)	25	25 ± 10 (14 - 52)	5	37 ± 25 (12 - 77)
GI Tract	1	22 (N/A)	1	22 (N/A)	0	N/A
Oral	23	25 ± 8 (16 - 52)	21	24 ± 8 (16 - 52)	2	25 ± 13 (16 - 35)
Gynecologic	58	27 ± 13 (12 - 69)	33	27 ± 16 (12 - 69)	25	26 ± 8 (12 - 52)
Other*	19	25 ± 7 (16 - 37)	14	27 ± 7 (19 - 37)	5	19 ± 4 (16 - 26)

**“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

NDC Number	Size	Protein Amount
67467-182-01 67467-182-02	500 IU VWF:RCo and 500 IU FVIII activities in 5 mL 1000 IU VWF:RCo and 1000 IU FVIII activities in 10 mL	≤ 7.5 mg ≤ 15.0 mg

• 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 controll

Vemurafenib

Pronunciation: VEM-ue-RAF-e-nib
Generic Name: Vemurafenib
Brand Name: Zelboraf

Vemurafenib is used for:

Treating certain types of skin cancer. It may also be used for other conditions as determined by your doctor.

Vemurafenib is a kinase inhibitor. It works by preventing the growth of cancer cells.

Do NOT use Vemurafenib if:

• you are allergic to any ingredient in Vemurafenib


• you have a history of certain types of irregular heartbeat (eg, QT prolongation, long QT syndrome)


• you have uncorrected low blood electrolyte levels (eg, potassium, calcium, magnesium)


• you take arsenic, halofantrine, nilotinib, toremifene, or vandetanib, or any other medicine that may increase the risk of a certain type of irregular heartbeat (prolonged QT interval). Check with your doctor or pharmacist if you are unsure if any of your medicines may increase the risk of this type of irregular heartbeat

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

Before using Vemurafenib:

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

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


• if you are able to become pregnant


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


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


• if you have a history of heart problems (eg, congestive heart failure, slow or irregular heartbeat), liver or kidney problems, skin cancer, or low blood electrolyte levels (eg, calcium, potassium, magnesium)


• if you have skin problems or you have chronic sun exposure


• if you take any medicines to treat irregular heartbeat

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

• Arsenic, halofantrine, nilotinib, toremifene, or vandetanib because the risk of severe and possibly fatal irregular heartbeat may be increased


• Certain azole antifungals (eg, ketoconazole, itraconazole, voriconazole), clarithromycin, nefazodone, protease inhibitors (eg, boceprevir, ritonavir), or telithromycin because they may increase the risk of Vemurafenib's side effects


• Carbamazepine, hydantoins (eg, phenytoin), phenobarbital, primidone, rifabutin, rifampin, rifapentine, or St. John's wort because they may decrease Vemurafenib's effectiveness


• Anticoagulants (eg, warfarin) or theophyllines (eg, aminophylline) because the risk of their side effects may be increased by Vemurafenib

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

How to use Vemurafenib:

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

• Vemurafenib comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Vemurafenib refilled.


• Take Vemurafenib by mouth with or without food.


• Swallow Vemurafenib whole with a glass of water. Do not break, crush, or chew before swallowing.


• Take Vemurafenib in the morning and in the evening, about 12 hours apart unless your doctor directs you otherwise.


• Continue to take Vemurafenib even if you feel well. Do not miss any doses.


• If you miss a dose of Vemurafenib, take it as soon as possible. If it is within 4 hours of your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

• Vemurafenib may cause dizziness, tiredness, weakness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Vemurafenib with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose, change your dose, or stop taking Vemurafenib without checking with your doctor.


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


• Cases of a certain other type of skin cancer have been reported with the use of Vemurafenib. The risk may be greater in elderly patients and in patients with chronic sun exposure or with a history of skin cancer. Contact your doctor right away if you experience a new wart, a change in size or color of a mole, or any other skin changes (eg, skin sore or reddish bump that bleeds or does not heal).


• Vemurafenib may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Vemurafenib. Use a sunscreen and lip balm, and wear protective clothing if you must be outside for more than a short time.


• Women who may become pregnant and men must use an effective form of birth control while taking Vemurafenib and for at least 2 months after stopping it. If you have questions about effective birth control, talk with your doctor.


• Lab tests, including electrocardiograms (ECGs), liver function, eye exams, blood electrolyte levels, and skin evaluations, may be performed while you use Vemurafenib. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Vemurafenib with caution in the ELDERLY; they may be more sensitive to its effects, especially a certain other type of skin cancer; nausea; loss of appetite; swelling of the hands, feet, or ankles; and irregular heartbeat.


• Vemurafenib should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Vemurafenib may cause harm to the fetus. Do not become pregnant or father a child while you are taking it or for at least 2 months after you stop taking it. If you think you may be pregnant or if your sexual partner becomes pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Vemurafenib while you are pregnant. It is not known if Vemurafenib is found in breast milk. Do not breast-feed while taking Vemurafenib.

Possible side effects of Vemurafenib:

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

Back pain; constipation; cough; diarrhea; dizziness; dry skin; hair loss; headache; joint or muscle pain; loss of appetite; nausea; taste changes; thickening of the skin; tiredness; vomiting; weakness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest or throat; swelling of the mouth, face, lips, or tongue; unusual hoarseness); burning, numbness, or tingling; eye pain, swelling, or redness; fainting; fast or irregular heartbeat; fever; light-headedness; mouth sores or blisters; red, swollen, blistered, or peeling skin; severe or persistent dizziness; swelling of the hands, feet, or ankles; symptoms of liver problems (eg, dark urine; pale stools; yellowing of the eyes or skin; unusual tiredness, nausea, or vomiting; persistent loss of appetite; severe stomach pain); tingling, pain, redness, or swelling of the palms of the hands and soles of the feet; vision changes (eg, blurred vision, sensitivity to light).

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

See also: Vemurafenib side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Vemurafenib:

Store Vemurafenib at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Vemurafenib in the original container with the lid tightly closed. Keep Vemurafenib out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Vemurafenib resources

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

• Vemurafenib Professional Patient Advice (Wolters Kluwer)


• vemurafenib Advanced Consumer (Micromedex) - Includes Dosage Information


• Zelboraf Prescribing Information (FDA)


• Zelboraf Consumer Overview

Compare Vemurafenib with other medications

• Melanoma, Metastatic

Vitafol-OB

Generic Name: prenatal multivitamins (PRE nay tal VYE ta mins)

Brand Names: Advance Care Plus, Bright Beginnings, Cavan Folate, Cavan One, Cavan-Heme OB, Cenogen Ultra, CitraNatal Rx, Co Natal FA, Complete Natal DHA, Complete-RF, CompleteNate, Concept OB, Docosavit, Dualvit OB, Duet, Edge OB, Elite OB 400, Femecal OB, Folbecal, Folcaps Care One, Folivan-OB, Foltabs, Gesticare, Icar Prenatal, Icare Prenatal Rx, Inatal Advance, Infanate DHA, Kolnatal DHA, Lactocal-F, Marnatal-F, Maternity, Maxinate, Mission Prenatal, Multi-Nate 30, Multinatal Plus, Nata 29 Prenatal, Natachew, Natafort, Natelle, Neevo, Nestabs, Nexa Select with DHA, Novanatal, NovaStart, O-Cal Prenatal, OB Complete, OB Natal One, Ob-20, Obtrex DHA, OptiNate, Paire OB Plus DHA, PNV Select, PNV-Total, PR Natal 400, Pre-H-Cal, Precare, PreferaOB, Premesis Rx, PrenaCare, PrenaFirst, PrenaPlus, Prenatabs OBN, Prenatabs Rx, Prenatal 1 Plus 1, Prenatal Elite, Prenatal Multivitamins, Prenatal Plus, Prenatal S, Prenatal-U, Prenate Advanced Formula, Prenate DHA, Prenate Elite, Prenavite FC, PreNexa, PreQue 10, Previte Rx, PrimaCare, Pruet DHA, RE OB Plus DHA, Renate, RightStep, Rovin-NV, Se-Care, Se-Natal One, Se-Plete DHA, Se-Tan DHA, Select-OB, Seton ET, Strongstart, Stuart Prenatal with Beta Carotene, Tandem OB, Taron-BC, Tri Rx, TriAdvance, TriCare, Trimesis Rx, Trinate, Triveen-PRx RNF, UltimateCare Advance, Ultra-Natal, Vemavite PRX 2, VeNatal FA, Verotin-BY, Verotin-GR, Vinacal OR, Vinatal Forte, Vinate Advanced (New Formula), Vinate AZ, Vinate Care, Vinate Good Start, Vinate II (New Formula), Vinate III, Vinate One, Vitafol-OB, VitaNatal OB plus DHA, Vitaphil, Vitaphil Aide, Vitaphil Plus DHA, Vitaspire, Viva DHA, Vol-Nate, Vol-Plus, Vol-Tab Rx, Vynatal F.A., Zatean-CH, Zatean-PN

What are Vitafol-OB (prenatal multivitamins)?

There are many brands and forms of prenatal vitamin available and not all brands are listed on this leaflet.

Prenatal vitamins are a combination of many different vitamins that are normally found in foods and other natural sources.

Prenatal vitamins are used to provide the additional vitamins needed during pregnancy. Minerals may also be contained in prenatal multivitamins.

Prenatal vitamins may also be used for purposes not listed in this medication guide.

What is the most important information I should know about prenatal vitamins?

There are many brands and forms of prenatal vitamin available and not all brands are listed on this leaflet.

Never take more than the recommended dose of a multivitamin. Avoid taking any other multivitamin product within 2 hours before or after you take your prenatal vitamins. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Many multivitamin products also contain minerals such as calcium, iron, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects and can also harm your unborn baby. Certain minerals contained in a prenatal multivitamin may also cause serious overdose symptoms or harm to the baby if you take too much.

Overdose symptoms may include stomach pain, vomiting, diarrhea, constipation, loss of appetite, hair loss, peeling skin, tingly feeling in or around your mouth, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine, pale skin, and easy bruising or bleeding.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin.

What should I discuss with my healthcare provider before taking prenatal vitamins?

Many vitamins can cause serious or life-threatening side effects if taken in large doses. Do not take more of this medication than directed on the label or prescribed by your doctor.

Before taking prenatal vitamins, tell your doctor about all of your medical conditions.

You may need to continue taking prenatal vitamins if you breast-feed your baby. Ask your doctor about taking this medication while breast-feeding.

How should I take prenatal vitamins?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Never take more than the recommended dose of prenatal vitamins.

Many multivitamin products also contain minerals such as calcium, iron, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Take your prenatal vitamin with a full glass of water.

Swallow the regular tablet or capsule whole. Do not break, chew, crush, or open it.

The chewable tablet must be chewed or allowed to dissolve in your mouth before swallowing. You may also allow the chewable tablet to dissolve in drinking water, fruit juice, or infant formula (but not milk or other dairy products). Drink this mixture right away.

Use prenatal vitamins regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store at room temperature away from moisture and heat. Keep prenatal vitamins in their original container. Storing vitamins in a glass container can ruin the medication.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects and can also harm your unborn baby. Certain minerals contained in a prenatal multivitamin may also cause serious overdose symptoms or harm to the baby if you take too much.

Overdose symptoms may include stomach pain, vomiting, diarrhea, constipation, loss of appetite, hair loss, peeling skin, tingly feeling in or around your mouth, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine, pale skin, and easy bruising or bleeding.

What should I avoid while taking prenatal vitamins?

Avoid taking any other multivitamin product within 2 hours before or after you take your prenatal vitamins. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Avoid the regular use of salt substitutes in your diet if your multivitamin contains potassium. If you are on a low-salt diet, ask your doctor before taking a vitamin or mineral supplement.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the prenatal vitamin.

Prenatal vitamins side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

When taken as directed, prenatal vitamins are not expected to cause serious side effects. Less serious side effects may include:

• 
  

  upset stomach;

  
  


• 
  

  headache; or

  
  


• 
  

  unusual or unpleasant taste in your mouth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect prenatal vitamins?

Vitamin and mineral supplements can interact with certain medications, or affect how medications work in your body. Before taking a prenatal vitamin, tell your doctor if you also use:

• 
  

  diuretics (water pills);

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  tretinoin (Vesanoid);

  
  


• 
  

  isotretinoin (Accutane, Amnesteen, Clavaris, Sotret);

  
  


• 
  

  trimethoprim and sulfamethoxazole (Cotrim, Bactrim, Gantanol, Gantrisin, Septra, TMP/SMX); or

  
  


• 
  

  an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

  
  

This list is not complete and other drugs may interact with prenatal vitamins. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Vitafol-OB resources

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

• Cal-Nate MedFacts Consumer Leaflet (Wolters Kluwer)


• CareNatal DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• CitraNatal 90 DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• CitraNatal Assure Prescribing Information (FDA)


• CitraNatal Harmony Prescribing Information (FDA)


• Concept DHA Prescribing Information (FDA)


• Docosavit Prescribing Information (FDA)


• Duet DHA with Ferrazone MedFacts Consumer Leaflet (Wolters Kluwer)


• Folbecal MedFacts Consumer Leaflet (Wolters Kluwer)


• Folcal DHA Prescribing Information (FDA)


• Folcaps Care One Prescribing Information (FDA)


• Gesticare DHA Prescribing Information (FDA)


• Gesticare DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• Inatal Advance Prescribing Information (FDA)


• Inatal Ultra Prescribing Information (FDA)


• Multi-Nate DHA Prescribing Information (FDA)


• Multi-Nate DHA Extra Prescribing Information (FDA)


• MultiNatal Plus MedFacts Consumer Leaflet (Wolters Kluwer)


• Natelle One Prescribing Information (FDA)


• Neevo Caplets MedFacts Consumer Leaflet (Wolters Kluwer)


• Neevo DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• OB Complete 400 MedFacts Consumer Leaflet (Wolters Kluwer)


• Paire OB Plus DHA Prescribing Information (FDA)


• PreNexa MedFacts Consumer Leaflet (Wolters Kluwer)


• PreNexa Prescribing Information (FDA)


• PreferaOB Prescribing Information (FDA)


• Prenatal Plus Prescribing Information (FDA)


• Prenatal Plus Iron Prescribing Information (FDA)


• Prenate Elite Prescribing Information (FDA)


• Prenate Elite MedFacts Consumer Leaflet (Wolters Kluwer)


• Prenate Elite tablets


• Prenate Essential Prescribing Information (FDA)


• PrimaCare Advantage MedFacts Consumer Leaflet (Wolters Kluwer)


• PrimaCare ONE capsules


• PrimaCare One MedFacts Consumer Leaflet (Wolters Kluwer)


• Renate DHA Prescribing Information (FDA)


• Se-Natal 19 Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Se-Natal 19 Prescribing Information (FDA)


• Tandem DHA Prescribing Information (FDA)


• Tandem OB Prescribing Information (FDA)


• TriAdvance Prescribing Information (FDA)


• Triveen-One MedFacts Consumer Leaflet (Wolters Kluwer)


• Triveen-PRx RNF Prescribing Information (FDA)


• UltimateCare ONE NF Prescribing Information (FDA)


• Ultra NatalCare MedFacts Consumer Leaflet (Wolters Kluwer)


• Vinate AZ Prescribing Information (FDA)


• Vitafol-One MedFacts Consumer Leaflet (Wolters Kluwer)


• Zatean-CH Prescribing Information (FDA)

Compare Vitafol-OB with other medications

• Vitamin/Mineral Supplementation during Pregnancy/Lactation

Where can I get more information?

• Your pharmacist can provide more information about prenatal vitamins.

See also: Vitafol-OB side effects (in more detail)

Victrelis

Generic Name: boceprevir (Oral route)

boe-SE-pre-vir

Commonly used brand name(s)

In the U.S.

• Victrelis

Available Dosage Forms:

• Capsule

Pharmacologic Class: Protease Inhibitor

Uses For Victrelis

Boceprevir is used in combination with injectable peginterferon alfa (Pegasys®, Pegintron®) and ribavirin (Copegus®, Rebetol®) to treat chronic hepatitis C infection. These medicines are used in patients with compensated liver disease (including cirrhosis), who have not been treated before or who have received other medicines but did not work well. Boceprevir is a direct-acting antiviral agent that treats hepatitis C infection.

This medicine is available only with your doctor's prescription.

Before Using Victrelis

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of boceprevir in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of boceprevir have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have age-related liver problems, which may require caution in patients receiving boceprevir.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin


• Carbamazepine


• Cisapride


• Colchicine


• Dihydroergotamine


• Drospirenone


• Ergonovine


• Ergotamine


• Lovastatin


• Methylergonovine


• Midazolam


• Phenobarbital


• Phenytoin


• Pimozide


• Rifampin


• Sildenafil


• Simvastatin


• St John's Wort


• Tadalafil


• Triazolam

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

• Alprazolam


• Amiodarone


• Bepridil


• Budesonide


• Dexamethasone


• Digoxin


• Efavirenz


• Ethinyl Estradiol


• Flecainide


• Fluticasone


• Itraconazole


• Posaconazole


• Propafenone


• Quinidine


• Rifabutin


• Ruxolitinib


• Salmeterol


• Sirolimus


• Sunitinib


• Vardenafil


• Voriconazole

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

• Ketoconazole

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Blood or bone marrow problems (e.g., anemia, neutropenia)—Use with caution. May make these conditions worse.

Proper Use of Victrelis

To help clear up your infection completely, boceprevir must be taken together with peginterferon alfa and ribavirin for the full time of treatment, even if you begin to feel better after a few days. Also, it is important to keep the amount of medicine in your body at a steady level. To help keep the amount constant, boceprevir must be used on a regular schedule.

Take this medicine with a meal or light snack.

Do not change or suddenly stop using this medicine without checking first with your doctor.

This medicine should come with a Medication Guide. Read and follow the information carefully. Ask your doctor if you have any questions. Ask your pharmacist for the Medication Guide if you do not have one.

Dosing

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

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

• For oral dosage form (capsules):
  
  • For hepatitis C virus infection, in combination with peginterferon alfa and ribavirin:
    
    • Adults—800 milligrams (mg) (four 200-mg capsules) three times a day with food. Each dose should be taken 7 to 9 hours apart.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose or forget to use it, and it is less than 2 hours before your next regular dose, wait until then to take the medicine and skip the missed dose. If you miss a dose and it is more than 2 hours before your next regular dose, go ahead and take the missed dose and take the next regular dose as scheduled. If you have any questions about this, ask your pharmacist or doctor.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Victrelis

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine together with peginterferon alfa and ribavirin while you are pregnant can harm your unborn baby. These medicines may also cause birth defects if the father is using it when his sexual partner becomes pregnant. If a pregnancy occurs while you are using these medicines, tell your doctor right away.

To make sure you are not pregnant, your doctor may ask you to have a pregnancy test before you start using this medicine. You must have a negative pregnancy test before you will be allowed to use this medicine with ribavirin. Two forms of birth control must be used during treatment and for 6 months after treatment ends. You should test for pregnancy every month while you are using this medicine, and for 6 months after your treatment ends.

Birth control pills may not work while you are using this medicine. To keep from getting pregnant, use two other forms of birth control. Other forms of birth control include condoms, diaphragms, or contraceptive foams or jellies.

Do not use this medicine together with the following medicines: alfuzosin (Uroxatral®), cisapride (Propulsid®), drospirenone (Yasmin®, Yaz®), oral midazolam (Versed®), pimozide (Orap®), rifampin (Rifadin®, Rimactane®), sildenafil (Revatio®), St. John's wort, tadalafil (Adcirca®), triazolam (Halcion®), certain medicines to lower cholesterol (such as lovastatin, simvastatin, Mevacor®, or Zocor®), medicines to treat seizures (such as carbamazepine, phenobarbital, phenytoin, Dilantin®, or Tegretol®), or ergot medicines (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine, DHE 45®, Ergomar®, Ergotrate®, or Methergine®). Using boceprevir with any of these medicines can cause very serious medical problems.

Check with your doctor right away if you have back, leg, or stomach pains; bleeding gums; chills; dark urine; difficulty with breathing; fever; general body swelling; headache; loss of appetite; nausea or vomiting; nosebleeds; pale skin; sore throat; unusual tiredness or weakness; or yellowing of the eyes or skin. These could be symptoms of a blood disorder called anemia.

Birth control pills may not work while you are using this medicine. To keep from getting pregnant, use two other forms of birth control. Other forms of birth control include condoms, diaphragms, or contraceptive foams or jellies.

Using this medicine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets in the blood, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests.

This medicine will not keep you from giving hepatitis C to other people. Follow your doctor's instructions about how to prevent the spread of this infection.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Victrelis Side Effects

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

Check with your doctor immediately if any of the following side effects occur:

More common

• Black, tarry stools


• chills


• cough


• difficult or labored breathing


• fever


• lower back or side pain


• painful or difficult urination


• pale skin


• shortness of breath


• sore throat


• tightness in the chest


• troubled breathing with exertion


• ulcers, sores, or white spots in the mouth


• unusual bleeding or bruising


• unusual tiredness or weakness


• wheezing

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

More common

• Change in taste


• decreased appetite


• diarrhea


• difficulty with moving


• dizziness


• dry mouth


• dry skin


• hair loss or thinning of the hair


• irritability


• lack or loss of strength


• loss of taste


• muscle pain or stiffness


• nausea


• pain in the joints


• rash


• sleeplessness


• trouble sleeping


• unable to sleep


• vomiting

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

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

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