WinRho

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: INTRAVASCULAR HEMOLYSIS (IVH)

This warning does not apply to Rho(D)-negative patients treated for the suppression of Rh isoimmunization.

• Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho® SDF for immune thrombocytopenic purpura (ITP).


• IVH can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS).


• Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.


• Closely monitor patients treated with WinRho® SDF for ITP in a healthcare setting for at least eight hours after administration. A dipstick urinalysis to monitor for hematuria and hemoglobinuria is to be performed at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor the signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hemoglobinuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently. If signs and/or symptoms of IVH are present or suspected after WinRho® SDF administration, post-treatment laboratory tests should be performed including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect).

Indications and Usage for WinRho

WinRho® SDF is an Rho(D) Immune Globulin Intravenous (Human) (anti-D) product that is indicated for the treatment of ITP in Rho(D)-positive patients and for the suppression of Rh isoimmunization in non-sensitized Rho(D)-negative patients.

Treatment of ITP

WinRho® SDF is indicated for use in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage in the treatment of non-splenectomized, Rho(D)-positive

• children with chronic or acute ITP,


• adults with chronic ITP, or


• children and adults with ITP secondary to HIV infection

The safety and efficacy of WinRho® SDF have not been evaluated in clinical trials for patients with non-ITP causes of thrombocytopenia or in previously splenectomized patients or in patients who are Rho(D)-negative.

Supression of Rh Isoimmunization

Pregnancy and Other Obstetric Conditions

WinRho® SDF is indicated for the suppression of Rh isoimmunization in non-sensitized, Rho(D)-negative (D-negative) women with an Rh-incompatible pregnancy, including:

• Routine antepartum and postpartum Rh prophylaxis


• Rh prophylaxis in cases of:
  
  • Obstetric complication (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplancental hemorrhage resulting from antepartum hemorrhage)
  
  
  • Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma)
  
  

An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rho(D)-positive or Rho(D)-unknown or if the father is either Rho(D)-positive or Rho(D)-unknown.

Incompatible Transfusions

WinRho® SDF is indicated for the suppression of Rh isoimmunization in Rho(D)-negative individuals transfused with Rho(D)-positive red blood cells (RBCs) or blood components containing Rho(D)-positive RBCs.

WinRho®SDF is not indicated for use as immunoglobulin replacement therapy for immune globulin deficiency syndromes.

WinRho Dosage and Administration

Preparation and Handling

• Bring WinRho® SDF to room temperature prior to use.


• Inspect WinRho® SDF for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates.


• WinRho® SDF is for single use only. Discard any unused portion.


• The solution is ready to use, no reconstitution required. See Table 1 for the target fill volumes for each of the dosage sizes for WinRho® SDF.

Table 1 Liquid WinRho® SDF Dosage size and target fill volumes

Vial Size	Target Fill Volume
600 international unit (120 mcg)	0.5 mL
1,500 international unit (300 mcg)	1.3 mL
2,500 international unit (500 mcg)	2.2 mL
5,000 international unit (1,000 mcg)	4.4 mL
15,000 international unit (3,000 mcg)	13.0 mL

Note: Remove the entire contents of the vial to obtain the labelled dosage of WinRho® SDF. If partial vials are required for dosage calculation, withdraw the entire contents of the vial to ensure accurate calculation of the dosage requirement. For ease in withdrawing the contents of the vial, draw back the plunger of a sterile syringe (with the needle and needle cover in place) to admit air into the syringe. Depress the plunger of the syringe to inject air into the vial. Invert vial and aspirate contents of vial into syringe.

Treatment of ITP

ADMINISTER WinRho®  SDF BY THE INTRAVENOUS ROUTE ONLY (see Preparation and Handling [2.1] ). Do not administer intramuscularly.

• Administer the entire dose of WinRho® SDF into a suitable vein over three to five minutes.


• Administer WinRho® SDF separately from other drugs.


• If dilution of WinRho SDF is preferred prior to intravenous administration, use normal saline as diluent. Do not use Dextrose (5%) in water (D5W). No other diluents have been tested.

Initial Dosing: An initial dose of 250 international unit/kg (50 mcg/kg) body weight, given as a single injection is recommended for the treatment of ITP. The initial dose may be administered in two divided doses given on separate days, if desired. If the patient has a hemoglobin level less than 10 g/dL, a reduced dose of 125 to 200 international unit/kg (25 to 40 mcg/kg) should be given to minimize the risk of increasing the severity of anemia in the patient. All patients should be monitored to determine clinical response by assessing platelet counts, RBCs, hemoglobin (Hgb), and reticulocyte levels [see ].

Subsequent Dosing: If subsequent therapy is required to elevate platelet counts, an intravenous dose of 125 to 300 international unit/kg (25 to 60 mcg/kg) body weight of WinRho® SDF is recommended. The frequency of dosing and the dose used in maintenance therapy should be determined by the patient’s clinical response by assessing platelet counts, RBCs, Hgb, and reticulocyte levels.

If a patient responded to initial dose with a satisfactory increase in platelets, maintenance dose at 125 to 300 international unit/kg (25 to 60 mcg/kg), individualized based on platelet and Hgb levels. An international consensus report on the investigation and management of primary immune thrombocytopenia states that treatment is rarely indicated in patients with platelet counts above 50 x 109/L and this has been generally accepted as the threshold for satisfactory response.1 Evaluate whether patient responded with a satisfactory increase in platelets based on the clinical situation and bleeding risks for the individual patient.

If patient did not respond to initial dose, administer a subsequent dose based on Hgb:

If Hgb between 8-10 g/dL, redose between 125 to 200 international unit/kg (25 to 40 mcg/kg).

If Hgb >10 g/dL, redose between 250 to 300 international unit/kg (50 to 60 mcg/kg).

If Hgb < 8 g/dL, alternative treatments should be used.

The following equations are provided to determine the dosage and number of vials needed for the treatment of ITP:

• weight in lbs/2.21 = weight in kg


• weight in kg X selected international unit (mcg) dosing level = dosage


• dosage / vial size = number of vials needed

Safety and efficacy of WinRho® SDF  in the treatment of ITP at doses exceeding 300 international unit/kg (60 mcg/kg) has not been established.

Supression of Rh Isoimmunization

Intravenous or intramuscular use.

• For intravenous administration, administer WinRho® SDF separately from other drugs. WinRho® SDF should be administered at a rate of 2 mL per 5 to 15 seconds.


• For intramuscular administration, administer into the deltoid muscle of the upper arm or the anterolateral aspects of the upper thigh. Due to the risk of sciatic nerve injury, avoid the gluteal region. If the gluteal region is used, use only the upper, outer quadrant.

Pregnancy and other Obstetric Indications

Table 2 provides dosing guidelines based on the condition being treated.

Table 2 Obstetric Indications and Recommended Dose

Indication	Timing of Administration	Dose (Administer IM or IV)
Rh-incompatible Pregnancy:
Routine antepartum prophylaxis	28 weeks gestation*	1,500 international unit (300 mcg)
Postpartum (if newborn is Rho(D)-positive)	Within 72 hours of birth**	600 international unit (120 mcg)
Obstetric Conditions:
Threatened abortion at any time	Immediately	1,500 international unit (300 mcg)
Amniocentesis and chorionic villus sampling before 34 weeks gestation	Immediately after procedure†	1,500 international unit (300 mcg)
Abortion, amniocentesis, or any other manipulation after 34 weeks gestation	Within 72 hours	600 international unit (120 mcg)
* If WinRho® SDF is administered early in the pregnancy, it is recommended that WinRho® SDF be administered at 12-week intervals in order to maintain adequate levels of passively acquired anti-Rh. ** In the event that the Rh status of the baby is not known at 72 hours, WinRho® SDF should be administered to the mother at 72 hours after delivery. If more than 72 hours have elapsed, WinRho® SDF should not be withheld but administered as soon as possible up to 28 days after delivery. †Repeat every 12 weeks during pregnancy

 Incompatible Transfusion

Administer WinRho® SDF within 72 hours after exposure for treatment of incompatible blood transfusions or massive fetal hemorrhage.

Table 3 provides dosing guidelines based on the condition being treated.

Table 3 Transfusion Indication and Recommended Dose

Route of Administration	Rate of Administration	WinRho® SDF Dose
		If exposed to Rho(D)-Positive Whole Blood:	If exposed to Rho(D)-Positive Red Blood Cells:
Intravenous	3,000 international unit (600 mcg) every 8 hours	45 international unit (9 mcg)/mL blood	90 international unit (18 mcg)/mL cells
Intramuscular	6,000 international unit (1,200 mcg) every 12 hours	60 international unit (12 mcg)/mL blood	120 international unit (24 mcg)/mL cells

Dosage Forms and Strengths

WinRho SDF, RhO(D) Immune Globulin Intravenous (Human), is available as a ready to use solution for injection available in single dose vials of 600 international unit (120 mcg), 1,500 international unit (300 mcg), 2,500 international unit (500 mcg), 5,000 international unit (1000 mcg) and 15,000 international unit (3,000 mcg).

Contraindications

WinRho® SDF is contraindicated in:

• Patients who have had known anaphylactic or severe systemic reaction to the administration of human immune globulin products.


• IgA deficient patients with antibodies to IgA and a history of hypersensitivity.


• Patients with autoimmune hemolytic anemia, with pre-existing hemolysis or at high risk for hemolysis.


• Infants for the suppression of Rho(D) isoimmunization.

Warnings and Precautions

Both Indications

5.1.1 Hypersensitivity

Severe hypersensitivity reactions may occur [see Contraindications (4)] If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue WinRho® SDF infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reactions.

WinRho® SDF contains approximately 5 micrograms/mL IgA [see Description (11)]. Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. WinRho® SDF is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4)].

5.1.2 Transmissible Infectious Agents

Because WinRho® SDF is made from human plasma; it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain pathogens, testing for the presence of certain current viral infections, and including virus inactivation/removal steps in the manufacturing process [see Description (11)]

Report all infections thought to have been transmitted by WinRho® SDF to Cangene Corporation at 1-800-768-2304. The physician should discuss the risks and benefits of this product with the patient.

5.1.3 Interference with Blood Glucose Testing: False High Blood Glucose Levels

The liquid formulation of WinRho® SDF contains maltose. Maltose in IGIV products has been shown to give falsely high blood glucose levels in certain types of blood glucose testing systems [for example, by systems based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods]. Due to the potential for falsely elevated glucose readings, only use testing systems that are glucose-specific to test or monitor blood glucose levels in patients receiving maltose-containing parenteral products, including WinRho® SDF Liquid.

Carefully review the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

5.1.4 Renal Dysfunction/Failure

Acute renal dysfunction/failure, osmotic nephropathy, and death may occur upon use of Immune Globulin Intravenous (IGIV) products, including WinRho® SDF.2 Ensure that patients are not volume depleted before administering WinRho® SDF. For patients at risk of renal dysfunction or failure, including those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs, administer WinRho® SDF at the minimum infusion rate practicable.

Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of WinRho® SDF.

5.1.5 Thromboembolic Events

Thromboembolic events may occur during or following treatment with WinRho® SDF and other IGIV products.3,4 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients who are at risk of developing thromboembolic events, administer WinRho® SDF at the minimum rate of infusion practicable.

5.1.6 Interference with Serological Testing

After administration of WinRho® SDF, a transitory increase of various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, C and E) and other blood group antibodies [for example, anti Duffy, anti Kidd (anti JKa) antibodies]5 may cause a positive direct or indirect (Coombs’) test.

A large fetomaternal hemorrhage late in pregnancy or following delivery may cause a weak mixed field positive Du test result. Assess such an individual for a large fetomaternal hemorrhage and adjust the dose of WinRho® SDF accordingly. The presence of passively administered anti Rho(D) in maternal or fetal blood can lead to a positive direct Coombs’ test. If there is an uncertainty about the father’s Rh group or immune status, administer WinRho® SDF to the mother.

5.1.7 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema may occur in patients following IGIV treatment, including WinRho® SDF.6 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following administration of blood products.

Monitor patients for pulmonary adverse reaction. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.1.8 Monitoring Laboratory Tests

• For all ITP patients, blood type, blood count, reticulocyte count, DAT and dipstick urinalysis are recommended before deciding to treat patients with WinRho® SDF. In patients with evidence of hemolysis (reticulocytosis greater than 3%), or patients at risk of hemolysis (positive DAT not attributed to previous immune globulin administration) use other treatments.1


• Closely monitor patients administered WinRho® SDF for at least 8 hours post administration and perform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period.


• If signs and/or symptoms of IVH and its complications are present after anti-D administration, perform appropriate confirmatory laboratory testing including, but not limited to, CBC (i.e. hemoglobin, platelet counts), haptoglobin, plasma hemoglobin, urine dipstick, assessment of renal function (i.e. BUN, serum creatinine), liver function (i.e. LDH, direct and indirect bilirubin) and DIC specific tests such as D-dimer or Fibrin Degradation Products (FDP) or Fibrin Split Products (FSP).


• Periodic monitoring of renal function and urine output in patients who are at increased risk of developing acute renal failure [see Warnings and Precautions (5.1.4)]. Assess renal function in these at-risk patients, including measurement of BUN and serum creatinine, before the initial infusion of WinRho® SDF and at appropriate intervals thereafter.


• If TRALI is suspected in ITP patients, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient serum [see Warnings and Precautions (5.1.7)].

Treatment of ITP

5.2.1 Intravascular Hemolysis (IVH)

IVH leading to death has been reported in patients treated for ITP with WinRho® SDF.

IVH can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS).

Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.7,8

Closely monitor patients treated with WinRho® SDF for ITP in a healthcare setting for at least eight hours after administration. Peform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor for signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hemoglobinuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently. If signs and/or symptoms of IVH are present or if IVH is suspected after WinRho® SDF administration, perform post-treatment laboratory tests including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect).

5.2.2 Hemolysis

Although the mechanism of action of WinRho® SDF in the treatment of ITP is not completely understood it is postulated that anti-D binds to the Rho(D) RBC resulting in formation of antibody-coated RBC complexes. Immune-mediated clearance of the antibody-coated RBC complexes would spare the antibody-coated platelets because of the preferential destruction of antibody-coated RBC complexes by the macrophages located in the reticuloendothelial system.9-11 The side effect of this action is a decrease in hemoglobin levels (extravascular hemolysis).7 The pooled data from ITP clinical studies demonstrated a mean decrease from baseline in hemoglobin levels of 1.2 g/dL within 7 days after administration of WinRho®SDF.

If the patient has lower than normal hemoglobin levels (less than 10 g/dL), a reduced dose of 125 to 200 international unit/kg (25 to 40 mcg/kg) should be given to minimize the risk of increasing the severity of anemia in the patient. Alternative treatments should be used in patients with hemoglobin levels that are less than 8 g/dL due to the risk of increasing the severity of the anemia [see Dosage and Administration (2.2)].

Significant anemia may present with pallor, hypotension, or tachycardia while acute renal insufficiency may present with oliguria or anuria, edema and dyspnea. Patients with IVH who develop DIC may exhibit signs and symptoms of increased bruising and prolongation of bleeding time and clotting time which may be difficult to detect in the ITP population. Consequently the diagnosis of this serious complication of IVH is dependent on laboratory testing [see Warnings and Precautions (5.1.7)]. Previous uneventful administration of WinRho® SDF does not preclude the possibility of an occurrence of IVH and its complications following any subsequent administration of WinRho® SDF. Have confirmatory laboratory testing on ITP patients presenting with signs and/or symptoms of IVH and its complications after anti-D administration [see Warnings and Precautions (5.1.7)].

If ITP patients are to be transfused, use Rho(D)-negative red blood cells (PRBCs) so as not to exacerbate ongoing hemolysis.

Supression of Rh Isoimmunization

Do not administer WinRho® SDF to Rho(D)-negative individuals who are Rh immunized as evidenced by an indirect antiglobulin (Coombs’) test revealing the presence of anti-Rho(D) (anti-D) antibody. For postpartum use following an Rh-incompatible pregnancy administer WinRho® SDF to the mother only. Do not administer to the newborn infant.

Adverse Reactions

Serious adverse reactions, some of these cases resulted in fatal outcome, have been observed in patients receiving WinRho® SDF for the treatment of ITP. These include: intravascular hemolysis (IVH), clinically compromising anemia, acute renal insufficiency and DIC [see Adverse Reactions, (6.2)].

The most common adverse reactions observed for all indications are: headache, chills, fever, asthenia, pallor, diarrhea, nausea, vomiting, arthralgia, myalgia, dizziness, hyperkinesia, abdominal or back pain, hypotension, hypertension, increased LDH, somnolence, vasodilation, pruritus, rash and sweating. All adverse reactions listed occurred in ≤ 2% of WinRho® doses administered in clinical trials.

Adverse reactions observed in the use of WinRho® SDF for Suppression of Rh Isoimmunization are <0.1% in Rho(D)-negative individuals.

Clinical Trials Experiences

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

Treatment of ITP

The safety of WinRho SDF was evaluated in clinical trials (n=161) in children and adults with acute and chronic ITP and adults and children with ITP secondary to HIV. Overall, 417 adverse events were reported by 91 patients (57%). The most common adverse events were headache (14% of the patients), fever (11% of the patients) and asthenia (11% of the patients). A total of 117 adverse drug reactions were re ported by 46 patients (29%). Headache, chills, and fever were the most common related adverse events (Table 4). With respect to safety profile per administration, 60/848 (7%) of WinRho® infusions had at least one adverse reaction. The most common adverse reactions were headache (19 infusions; 2%), chills (14 infusions; < 2%), and fever (nine infusions; 1%).

Table 4 Adverse drug Reaction s with an Incidence ≥5% of Patients

Body System	Adverse Event	All Studies	Children	Adults
		# of Patients (%)
Body as a Whole	Headache	18 (11)	8 (11)	10 (12)
	Chills	13 (8)	4 (5)	9 (10)
	Fever	9 (6)	5 (7)	4 (5)
	Asthenia	6 (4)	2 (3)	4 (5)
	Infection	4 (3)	4 (5)	0 (0)
Nervous System	Dizziness	6 (4)	2 (3)	4 (5)

 

In four clinical trials of patients treated with the recommended initial intravenous dose of 250 international unit/kg (50 mcg/kg), the mean maximum decrease in hemoglobin was 1.70 g/dL (range: +0.40 to -6.1g/dL). At a reduced dose, ranging from 125 to 200 international unit/kg (25 to 40 mcg/kg), the mean maximum decrease in hemoglobin was 0.81 g/dL (range: +0.65 to -1.9 g/dL). Only 5/137 (3.7%) of patients had a maximum decrease in hemoglobin of greater than 4 g/dL (range: -4.2 to -6.1 g/dL).

Suppression of Rh Isoimmunization

In the clinical trial of 1,186 Rho(D)-negative pregnant women, no adverse reactions were reported to Rho(D) IGIV.

Post-marketing Experience

Because post-marketing adverse 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. The following adverse reactions have been identified during the post-approval use of WinRho®  SDF.

Treatment of ITP

These adverse reactions are classified by system organ class.

Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho® SDF for immune thrombocytopenic purpura (ITP).

Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.

Infusion Reactions: Anaphylactic reaction, Hypersensitivity

Hematologic: Intravascular hemolysis, Disseminated Intravascular Coagulation, Hemoglobinemia

Cardiac: Cardiac arrest, Cardiac failure, Myocardial infarction, Tachycardia

Gastrointestinal: Nausea

General: Chest pain, Fatigue, Edema

Hepatologic: Jaundice

Musculoskeletal: Myalgia, Muscle spasm, Pain in extremities

Renal: Renal failure, Renal impairment, Anuria, Chromaturia, Hemoglobinuria, Hematuria

Respiratory: Acute respiratory distress syndrome, Transfusion related acute lung injury

Integumentary: Hyperhidrosis

Suppression of Rh Isoimmunization

Infusion Reactions: Hypersensitivity, anaphylactic reaction, induration, pruritus or swelling at injection site

Integumentary: Pruritus, Rash

Healthcare professionals should report serious adverse reactions following the administration of WinRho® SDF to Cangene Corporation at 1-800-768-2304 or FDA’s MedWatch reporting system by phone (1-800-FDA-1088).

Drug Interactions

Live Virus Vaccines

Administration of WinRho® SDF concomitantly with other drugs has not been evaluated. Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella (see Patient Counseling Information [17.1]). Do not give immunization with live vaccines within 3 months after WinRho® SDF administration.

USE IN SPECIFIC POPULATIONS

Pregnancy

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

Treatment of ITP

WinRho® SDF has not been evaluated in pregnant women with ITP.

Suppression of Rh Isoimmunization

The available evidence suggests that WinRho® SDF does not harm the fetus or affect future pregnancies or reproduction capacity when given to pregnant Rho(D)-negative women for suppression of Rh isoimmunization.12

Nursing Mothers

Treatment of ITP

WinRho® SDF has not been evaluated in nursing mothers with ITP.

Suppression of Rh Isoimmunization

It is not known whether WinRho® SDF is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when WinRho SDF is administered to nursing women.

Pediatric Use

The safety and effectiveness of WinRho® has been evaluated for the treatment of chronic or acute ITP in children and in children (<16 years of age) with ITP secondary to HIV infection [see Adverse Reactions (6.2)]. The dosing recommendation in the treatment of children with ITP is the same as in adults [see Dosage and Administration (2.2)].

Geriatric Use

Clinical studies of WinRho® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post marketing clinical experience suggests that patients of advanced age (age over 65) with co-morbid conditions including but not limited to cardio-respiratory decompensation, renal failure or insufficiency or prothrombotic conditions are at increased risk of developing serious complications from acute hemolytic reactions such as IVH. Patients receiving doses in excess of 300 international unit/kg of WinRho® SDF may also be at an increased risk of developing increased hemolysis. Fatal outcomes associated with IVH and its complications have occurred most frequently in patients of advanced age (age over 65) with co-morbid conditions.

Use caution in dose selection for geriatric patients with consideration given to starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

Treatment of ITP and Suppression of Rh Isoimmunization

In post-marketing spontaneous reporting, there has been a limited number of medication error reports related to dosage calculations in which higher doses than that recommended for WinRho® SDF were administered (doses > 60 mcg/kg). Signs and laboratory findings of overdosage in Rh positive (ITP) patients have included hemoglobin decreases in excess of 1.2 g/dL. For the suppression of Rh isoimmunization, hemolytic reactions have been reported in cases of mis-matched blood transfusions where very large doses of WinRho SDF were administered.

In one ITP case report that involved an overdose due to confusion between mcg and international unit, a patient with significant co-morbidities developed IVH and had a fatal outcome. In the event of overdose, monitor patients closely for signs and symptoms of hemolysis and initiate symptomatic and supportive treatment.

WinRho Description

WinRho® SDF is a sterile, liquid gamma globulin (IgG) fraction containing antibodies to the Rho(D) antigen (D antigen). WinRho® SDF is to be administered intravenously for the treatment of ITP and either intravenously or intramuscularly for the suppression of Rh isoimmunization.

WinRho® SDF is prepared from human plasma by an anion-exchange column chromatography method. The manufacturing process includes two steps implemented specifically for viral clearance. The solvent detergent treatment step (using tri-n-butyl phosphate and Triton® X-100) is effective in inactivating lipid enveloped viruses such as hepatitis B, hepatitis C, and HIV. Virus filtration, using a Planova™ 20N virus filter is effective in the removal of some non-lipid enveloped viruses. These two processes are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses, respectively. In addition to the two specific steps, the anion-exchange chromatography step contributes to the removal of small non-lipid enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in Table 5.

Table 5 - Virus Reduction Values Obtained Through Validation Studies

Enveloped	Enveloped			Non-Enveloped
Genome	RNA		DNA	RNA		DNA
Virus	HIV-1	BVDV	PRV	HAV	EMC	MMV	PPV
Family	retro	flavi	herpes	picorna		parvo
Size (nm)	80-100	50-70	120-200	25-30	30	20-25	18-24
Anion Exchange Chromatography (partitioning)	Not evaluated			2.3	n.e.	3.4	n.e.
20N Filtration (size exclusion)	≥ 4.7	≥ 3.5	≥ 5.6*	n.e.	4.8	n.e.	4.1
Solvent/Detergent (inactivation)	≥ 4.7	≥ 7.3	≥ 5.5	Not evaluated
Total Reduction (log10)	≥ 9.4	≥ 10.8	≥ 11.1	7.1		7.5

* The PRV was retained by the 0.1 µm pre-filter during the virus validation. Since manufacturing employs a 0.1 µm pre-filter before the 20N filter, the claim of ≥5.6 reduction is considered applicable.

Abbreviations:

HIV-1: human immunodeficiency virus-1; relevant virus for human immunodeficiency virus-1 and model for HIV-2.

BVDV: bovine viral diarrhea virus; model virus for hepatitis C virus (HCV) and West Nile virus (WNV)

PRV: pseudorabies virus; model for large enveloped DNA viruses, including herpes

HAV: human hepatitis A virus; relevant virus for HAV and model for small non-enveloped viruses in general

EMC: encephalomyocarditis virus; model for HAV and for small non-enveloped viruses in general

MMV: murine minute virus; model for human parvovirus B19 and for small non-enveloped viruses in general

PPV: porcine parvovirus; model for human parvovirus B19 and for small non-enveloped viruses in general

n.e.: not evaluated

The product potency is expressed in international units by comparison to the World Health Organization (WHO) standard. In the past, a full dose of Rho(D) Immune Globulin (Human) has traditionally been referred to as a “300 microgram” dose. Potency and dosing recommendations are now expressed in international units by comparison to the WHO anti-Rho(D) standard. The conversion of “microgram” to “international units” is: 1 microgram = 5 international units. A 1,500 international unit (300 microgram [mcg]) vial contains sufficient anti-Rho(D) to effectively suppress the immunizing potential of approximately 17 mL of Rho(D) (D-positive) RBCs.

The liquid formulation is stabilized with 10% maltose and 0.03% polysorbate 80. There are no preservatives in the formulation. WinRho® SDF does not contain mercury. This product contains approximately 5 micrograms/mL IgA.

WinRho - Clinical Pharmacology

Mechanism of Action

Treatment of ITP

WinRho® SDF has been shown to increase platelet counts in non-splenectomized, Rho(D)-positive patients with ITP. Platelet counts usually rise within one to two days and peak within seven to 14 days after initiation of therapy. The mechanism of action is not completely understood, but is thought to be due to the formation of anti-Rho(D)-coated RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.9,10

Suppression of Rh Isoimmunization

The mechanism by which Rho(D) immune globulin suppresses immunization to Rho(D)-positive RBCs is not completely understood.

WinRho® SDF when administered within 72 hours of a full-term delivery of a Rho(D)-positive infant by a Rho(D) negative mother will reduce the incidence of Rh isoimmunization from 12-13% to 1-2%. The 1-2% is, for the most part, due to isoimmunization during the last trimester of pregnancy. When treatment is given both antenatally, at 28 weeks gestation, and postpartum, the Rh immunization rate drops to about 0.1%.13,14

When 600 international unit (120 mcg) of WinRho® SDF is administered to pregnant women, passive anti-Rho(D) antibodies are not detectable in the circulation for more than six weeks and therefore a dose of 1,500 international unit (300 mcg) should be used for antenatal administration.

Pharmacodynamics

In a clinical study with Rho(D)-negative volunteers (nine males and one female), Rho(D)-positive RBCs were completely cleared from the circulation within eight hours of intravenous administration of WinRho. There was no indication of Rh isoimmunization of these subjects at six m

Comfort Pac w/Tizanidine

Generic Name: tizanidine (Oral route)

tye-ZAN-i-deen

Commonly used brand name(s)

In the U.S.

• Comfort Pac w/Tizanidine


• Zanaflex


• Zanaflex Capsule

Available Dosage Forms:

• Capsule


• Tablet

Therapeutic Class: Skeletal Muscle Relaxant, Centrally Acting

Uses For Comfort Pac w/Tizanidine

Tizanidine is used to help relax certain muscles in your body. It relieves the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis or certain injuries to the spine. Tizanidine does not cure these problems, but it may allow other treatment, such as physical therapy, to be more helpful in improving your condition.

Tizanidine acts on the central nervous system (CNS) to produce its muscle relaxant effects. Its actions on the CNS may also cause some of the medicine's side effects.

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

Before Using Comfort Pac w/Tizanidine

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

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of tizanidine in children with use in other age groups.

Geriatric

Studies in older adults show that tizanidine stays in the body a little longer than it does in younger adults. Your doctor will consider this when deciding on your dose.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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.

• Ciprofloxacin


• Fluvoxamine

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.

• Acyclovir


• Amiodarone


• Cimetidine


• Desogestrel


• Dienogest


• Drospirenone


• Estradiol Cypionate


• Estradiol Valerate


• Ethinyl Estradiol


• Ethynodiol Diacetate


• Etonogestrel


• Famotidine


• Levonorgestrel


• Medroxyprogesterone Acetate


• Mestranol


• Mexiletine


• Norelgestromin


• Norethindrone


• Norfloxacin


• Norgestimate


• Norgestrel


• Ofloxacin


• Propafenone


• Rofecoxib


• Ticlopidine


• Vemurafenib


• Verapamil


• Zileuton

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.

• Fosphenytoin


• Lisinopril


• Phenytoin

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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:

• Kidney disease or


• Liver disease—The chance of side effects may be increased; higher blood levels of tizanidine may result and a smaller dose may be needed

Proper Use of tizanidine

This section provides information on the proper use of a number of products that contain tizanidine. It may not be specific to Comfort Pac w/Tizanidine. Please read with care.

When you take the different dosage forms (tablets, capsules, capsule contents sprinkled over applesauce) of tizanidine with food, it effects the amount of the medicine absorbed into your blood differently. Follow your doctor's instructions for when to take this medicine and whether or not you should take it with food.

Take this medicine only as directed. Do not take more of it and do not take it more often than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of side effects.

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 and tablets):
  
  • For muscle relaxation:
    
    • Adults—The dose is 8 milligrams (mg) every six to eight hours as needed. No more than 36 mg should be taken within a twenty-four-hour period.
    
    
    • 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.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Comfort Pac w/Tizanidine

Your doctor should check your progress at regular visits, especially during the first few weeks of treatment with this medicine. During this time the amount of medicine you are taking may have to be changed often to meet your individual needs.

Do not suddenly stop taking this medicine. Unwanted effects may occur if the medicine is stopped suddenly. Check with your doctor for the best way to reduce gradually the amount you are taking before stopping completely.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; other muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using tizanidine.

This medicine may cause dizziness, drowsiness, lightheadedness, clumsiness or unsteadiness, or vision problems in some people. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, and able to see well.

Tizanidine may cause dryness of the mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if dry mouth continues for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem.

Comfort Pac w/Tizanidine Side Effects

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

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Chest pain or discomfort


• fever


• loss of appetite


• lower back or side pain


• nausea and/or vomiting


• nervousness


• pain or burning while urinating


• painful or difficult urination


• sores on the skin


• tingling, burning, or prickling sensations


• unusual tiredness


• yellow eyes or skin

Less common

• Black, tarry stools


• bloody vomit


• blurred vision


• chills or sore throat


• coldness


• convulsions (seizures)


• cough or hoarseness


• dark urine


• dry, puffy skin


• eye pain


• fainting


• influenza (flu)-like symptoms


• irregular heartbeat


• kidney stones


• persistent anorexia


• pruritus


• right upper quadrant tenderness


• seeing things that are not there


• shortness of breath


• slow or irregular heartbeat


• unusual tiredness or weakness


• weight gain

Incidence not known

• Continuing vomiting


• general feeling of tiredness or weakness


• headache


• light-colored stools

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Blurred vision


• change in consciousness


• chest pain or discomfort


• confusion


• decreased awareness or responsiveness


• difficult or troubled breathing


• dizziness, faintness or lightheadedness when getting up from a lying position


• irregular, fast or slow, or shallow breathing


• lightheadedness, dizziness or fainting


• loss of consciousness


• pale or blue lips, fingernails, or skin


• severe sleepiness


• shortness of breath


• sleepiness or unusual drowsiness


• slow or irregular heartbeat


• sweating


• unusual tiredness or weakness

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

• Anxiety


• back pain


• constipation


• depression


• diarrhea


• difficulty in speaking


• dizziness or lightheadedness, especially when getting up from a lying or sitting position


• drowsiness


• dry mouth


• heartburn


• increased sweating


• increased muscle spasms or tone


• muscle weakness


• pain or burning in throat


• runny nose


• skin rash


• sleepiness


• stomach pain


• uncontrolled movements of the body

Less common

• Difficulty swallowing


• dry skin


• general feeling of discomfort or illness


• increased need to urinate


• joint or muscle pain or stiffness


• loss of hair


• migraine headache


• mood changes


• neck pain


• passing urine more often


• shivering


• swelling of feet or lower legs


• swollen area that feels warm and tender


• trembling or shaking


• trouble sleeping


• unusual feeling of well-being


• unusual tiredness or weakness


• weight loss

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

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

See also: Comfort Pac w/Tizanidine side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Comfort Pac w/Tizanidine resources

• Comfort Pac w/Tizanidine Side Effects (in more detail)
• Comfort Pac w/Tizanidine Use in Pregnancy & Breastfeeding
• Drug Images
• Comfort Pac w/Tizanidine Drug Interactions
• Comfort Pac w/Tizanidine Support Group
• 73 Reviews for Comfort Pac w/Tizanidine - Add your own review/rating

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