Kogenate FS

antihemophilic factor (recombinant)

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Kogenate FS

Control and Prevention of Bleeding Episodes

Kogenate® FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with hemophilia A.

Peri-operative Management

Kogenate FS is indicated for surgical prophylaxis in adults and children with hemophilia A.

Routine Prophylaxis in Children with Hemophilia A with No Pre-existing Joint Damage

Kogenate FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.

Kogenate FS is not indicated for the treatment of von Willebrand’s disease.

Kogenate FS Dosage and Administration

For Intravenous Use After Reconstitution

• Treatment with Kogenate FS should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.


• Each vial of Kogenate FS has the recombinant factor VIII (rFVIII) potency in international units stated on the label.


• Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. [See Table 1 and Table 2.]

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:

Dosage (units) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

OR

IU/dL (or % normal)=Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Examples (assuming patient’s baseline factor VIII level is <1% of normal):

1. A dose of 1750 IU Kogenate FS administered to a 70 kg patient should be expected to result in a peak post-infusion factor VIII increase of 1750 IU x {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal).


2. A peak level of 50% is required in a 15 kg child. In this situation, the appropriate dose would be:
   
   50 IU/dL/{[2 IU/dL]/[IU/kg]} x 15 kg = 375 IU.

Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Kogenate FS.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed. [See Warnings and Precautions (5.4) and Clinical Pharmacology (12.3).]

Control and Prevention of Bleeding Episodes

The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes or major surgery.

The following table can be used to guide dosing in bleeding episodes.

Table 1 Control and Prevention of Bleeding Episodes for Children and Adults

Type of Bleeding Episode	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Early hemarthrosis, minor muscle or oral bleeds.	20–40	10–20 IU per kg Repeat dose if there is evidence of further bleeding.
Moderate Bleeding  into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma.	30–60	15–30 IU per kg Repeat dose every 12–24 hours until bleeding is resolved.
Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath. Fractures. Head trauma.	80–100	Initial dose 40–50 IU per kg Repeat dose 20–25 IU per kg every 8–12 hours until bleeding is resolved.

 

Peri-operative Management

The careful control of treatment dose is especially important in cases of major surgery or life-threatening bleeding episodes.

The following table can be used to guide dosing in surgery:

Table 2 Peri-operative Management for Adults and Children

Type of Surgery	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Including tooth extraction	30–60	15–30 IU per kg Repeat dose every 12–24 hours until bleeding is resolved.
Major Examples include tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma.	100	Pre-operative dose 50 IU per kg Verify 100% activity prior to surgery. Repeat as necessary after 6 to 12 hours initially, and for 10 to 14 days until healing is complete.

Routine Prophylaxis in Children with No Pre-existing Joint Damage. 

The recommended dose for routine prophylaxis is 25 IU/kg of body weight every other day.5

Instructions for Use

Kogenate FS is administered by intravenous (IV) injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.

For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling. [See FDA-Approved Patient Labeling (17).]

Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS product, in an appropriate container.

Preparation and Reconstitution

The procedures below are provided as general guidelines for the reconstitution and administration of Kogenate FS with BIO-SET®, a needleless self-contained reconstitution system. Always work on a clean surface and wash hands before performing the following procedures.

Vacuum Transfer and Reconstitution

1. Warm the unopened diluent (as needed) and the concentrate to a temperature not to exceed 37°C or 99°F.


2. Remove the cap from the concentrate. Take out the prefilled diluent syringe and remove the tip cap. (Fig. A).


3. Connect the prefilled diluent syringe to the concentrate vial by gently screwing on to the BIO-SET connection (Fig. B).


4. Place the vial on a rigid, non-skid surface and hold it firmly with one hand. With the other hand, strongly press down the fingerplate near the syringe tip using your thumb and index finger (Fig. C) until the fingerplate meets the top edge of the BIO-SET. This confirms that the system is activated (Fig. D).


5. Grasp the plunger rod by the top plate and remove from carton. Avoid touching the sides and threads of the plunger rod. Immediately screw plunger rod into the syringe rubber stopper (Fig. E).


6. Inject the diluent into the concentrate by pushing down the plunger rod slowly (Fig. F).


7. Swirl gently until completely dissolved without creating excessive foaming (Fig. G).


8. Kogenate FS should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.


9. Invert vial/syringe and transfer the solution into syringe that was used to deliver the diluent (Fig. H). Ensure that the entire contents of the reconstituted Kogenate FS vial are drawn into the syringe.


10. Unscrew the filled syringe to disconnect it from the empty concentrate vial (Fig. I).


11. Attach the filled syringe to the administration set provided and immediately inject intravenously (Fig. J). NOTE: See accompanying instructions for Infusion Set with Filter.


12. If the same patient is to receive more than one vial, the diluent syringe provided should be used to reconstitute the powder in the product vials as described above. The reconstituted solutions should then be combined in a larger plastic syringe (not provided) and administered as usual (Fig. J).

Administration

For Intravenous Use Only After Reconstitution

• Kogenate FS should be inspected visually for particulate matter and discoloration prior to administration, wherever solution and container permit. Turbid or discolored solution should be discarded.


• Reconstituted Kogenate FS may be stored at room temperature prior to administration, but is to be administered within 3 hours. It is recommended to use the IV administration set provided.


• A dose of Kogenate FS may be administered over a period of 1 to 15 minutes. The rate of administration however, should be adapted to the response of each individual patient. The pulse rate should be determined before and during administration of Kogenate FS. If there is a significant increase in pulse rate, reducing the rate of administration or temporarily halting the injection allows the symptoms to disappear promptly.

Dosage Forms and Strengths

Kogenate FS is available as a lyophilized powder in single use glass vials containing 250, 500, 1000, 2000, and 3000 International Units (IU).

Each vial of Kogenate FS is labeled with the recombinant antihemophilic factor activity expressed in IU per vial. This potency assignment employs a factor VIII concentrate standard that is referenced to a WHO International Standard for factor VIII concentrates, and is evaluated by appropriate methodology to ensure accuracy of the results.

Contraindications

Kogenate FS is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including mouse or hamster proteins.

Warnings and Precautions

General

The clinical response to Kogenate FS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of Kogenate FS should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. [See Warnings and Precautions (5.4).]

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic-type hypersensitivity reactions including anaphylaxis have been reported with Kogenate FS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment.

Kogenate FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Neutralizing Antibodies

Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests.6 Inhibitors have been reported following administration of Kogenate FS predominantly in previously untreated patients. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed.[See Warnings and Precautions (5.4).]

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. [See Dosage and Administration (2).]


• Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of Kogenate FS. Use Bethesda Units ( BU) to titer inhibitors.
  
  • If the inhibitor is less than 10 BU per mL, the administration of additional Kogenate FS concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response.
  
  

Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

Adverse Reactions

The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF.

The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for intravenous administration.

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 clinical trials of another drug and may not reflect the rates observed in clinical practice.

Previously Treated Patients (PTPs)

During the clinical studies conducted in PTPs, 451 adverse events (irrespective of the relationship to the study drug) were reported in the course of 24,936 infusions (1.8%). Twenty-four of the 451 adverse events were assessed as related to Kogenate FS (0.1%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

Table 3 Adverse Reactions (AR) in Previously Treated Patients (PTPs) with Frequency of ≥ 4%

SOC = System Organ Class
MedDRA Primary SOC	Preferred Term	Total No. of Patients: 73 No. of Patients with AR (%)	Total No. of Infusions: 24,936 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus	6 (8.2%)	0.02
General Disorders and Administration Site Conditions	Infusion site reactions	3 (4.1%)	0.01

Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)

In clinical studies with pediatric PUPs and MTPs, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Twenty-nine of the 726 adverse events were assessed as related to Kogenate FS (0.3%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

Table 4 Adverse Reactions (AR) in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) with Frequency of ≥ 4% (Age Range 2-27 months)

SOC = System Organ Class
* *Denominator for de-novo inhibitors is N=60, since one patient had a pre-existing inhibitor.
MedDRA Primary SOC	Preferred Term	Total No. of patients: 61 No. of Patients with AR (%)	Total No. of Infusions: 9,389 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus, urticaria	10 (16.4)	0.01
Blood and Lymphatic System Disorders	Factor VIII inhibition	9 (15)*	N/A
General Disorders and Administration Site Conditions	Infusion site reactions	4 (6.6)	0.04

Minimally Treated Patients (MTPs) in the Joint Outcome Study

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Kogenate FS.

Table 5 Adverse Events (AE) in MTPs in the Joint Outcome Study (Age Range 0-6 years)

SOC = System Organ Class
* Three patients from the enhanced episodic arm had catheter removal.
MedDRA Primary SOC	Preferred Term	Total No. of Prophylaxis Arm Patients: 32 No. of Patients with AE (%)	Total No. of Enhanced Episodic Arm Patients: 33 No. of Patients with AE (%)
Surgical and Medical Procedures	Central venous catheterization, Catheter removal	19 (59)	18* (55)
Infections and Infestations	Central line infection	6 (19)	6 (18)
General Disorders and Administration Site Conditions	Pyrexia	1 (3)	4 (12)

Immunogenicity

In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de-novo inhibitors were observed.

In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (>5BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).

In the Joint Outcome Study with Kogenate FS,5 de-novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (>5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).

Post-Marketing Experience

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

Among patients treated with Kogenate FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates.

The following table represents the post-marketing adverse reactions as MedDRA Preferred Terms.

Table 6 Post-Marketing Experience

SOC = System Organ Class
MedDRA Primary SOC	Preferred Term
Blood and Lymphatic System Disorders	FVIII inhibition
Skin and Subcutaneous Tissue Disorders	Pruritus, urticaria, rash
General Disorders and Administration Site Conditions	Infusion site reaction
	Pyrexia
Immune System Disorders	Anaphylactic reaction, other hypersensitivity reactions

Drug Interactions

None known.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

Animal reproduction studies have not been conducted with Kogenate FS. It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Kogenate FS should be used during pregnancy only if clinically needed.

Labor and Delivery

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Kogenate FS should be used only if clinically needed.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Kogenate FS is administered to nursing mothers. Kogenate FS should be given to nursing mothers only if clinically needed.

Pediatric Use

Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children in comparison to adults present higher factor VIII clearance values and thus lower recovery of factor VIII. This may be explained by differences in body composition7 and should be taken into account when dosing or following factor VIII levels in such a population. [See Clinical Pharmacology ( 12.3).] Routine prophylactic treatment in children ages 0-2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5-16 years for children who have no existing joint damage. [See Clinical Studies (14.3).]

Geriatric Use

Clinical studies with Kogenate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.

Kogenate FS Description

Kogenate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced.8 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Kogenate FS.

The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.9-21 Several of the individual production and raw material preparation steps in the Kogenate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).

Kogenate FS is formulated with the following as stabilizers [see Table 7] in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for intravenous (IV) injection. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels.

Table 7 Stabilizers Contained in Kogenate FS Final Container

Stabilizer	250 IU, 500 IU, 1000 IU	2000 IU, 3000 IU
Sucrose	0.9–1.3%	0.9–1.2%
Glycine	21–25 mg/mL	20–24 mg/mL
Histidine	18–23 mmol/L	17–22 mmol/L

 The following inactive ingredients/excipients are also contained in the final product:

Table 8 Inactive Ingredients/Excipients

Inactive Ingredient/Excipient	250 IU, 500 IU, 1000 IU	2000 IU, 3000 IU
Sodium	27–36 mEq/L	26–34 mEq/L
Calcium	2.0–3.0 mmol/L	1.9–2.9 mmol/L
Chloride	32–40 mEq/L	31–38 mEq/L
Polysorbate 80	64–96 µg/mL	64–96 µg/mL
Sucrose	28 mg/vial	52 mg/vial
Imidazole, tri-n-butyl phosphate, and copper	Trace amounts	Trace amounts

 Each vial of Kogenate FS contains the labeled amount of recombinant factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

Kogenate FS - Clinical Pharmacology

Mechanism of Action

Kogenate FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.

Pharmacodynamics

The aPTT is prolonged in patients with hemophilia. Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay for biological activity of factor VIII. Treatment with Kogenate FS normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in previously treated patients, adults and children.

Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product with a single dose administration of 50 IU/kg. After 24 weeks, the same dose of Kogenate FS was administered to the same patients. The recovery and half-life data for Kogenate FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition. [See Table 9.]

Table 9 Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE

Parameter	Kogenate FS		KOGENATE
	Initial PK Mean (±SD)	PK at week 24 Mean (±SD)	Reference Mean (±SD)
AUC (IU • h/dL)	1588.05 ± 344.32	1487.08 ± 381.73	1879.02 ± 412.32
Cmax (IU/dL)	114.95 ± 20.19	109.42 ± 20.09	127.40 ± 33.21
Half-life (hr)	13.74 ± 1.82	14.60 ± 4.38	14.07 ± 2.62
In Vivo Recovery (IU/dL / IU/kg)	2.20 ± 0.34	2.11 ± 0.37	2.43 ± 0.60

 The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 10.

Table 10 Pharmacokinetic Parameters for Kogenate FS in Children

Parameter	Mean (range)
AUC (IU • h/dL)	1320.0
Clearance (mL/h•kg)	4.1
Half-life (hr)	10.7 (7.8–15.3)
In Vivo Recovery (IU/dL / IU/kg)	1.9 (1.25–2.76)

 

Nonclinical Toxicology

Preclinical studies evaluating Kogenate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Kogenate FS in laboratory animals.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Kogenate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. Kogenate FS has been shown to be comparable to the predecessor product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, the predecessor product and Kogenate FS would be expected to have equivalent mutagenic and carcinogenic potential.

The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

Clinical Studies

Previously Treated Patients

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Kogenate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week). [See Table 11.]

Table 11 Previously Treated Patients (PTPs) Clinical Trial Results

Clinical Parameters	Results
No. of Infusions of Kogenate FS Administered	24,924
No. of IU Administered	45 million IU
No. of Bleeds Treated with Kogenate FS	5,684
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS	one infusion: 79.7%, two infusions: 13.0% total: 92.7%
Mean Kogenate FS Dose per Treatment Infusion (in Europe and North America, Respectively)	Approximately 32.5 and 29.6 IU/kg per treatment infusion

 A total of 31 patients received Kogenate FS for 43 surgical procedures during the PTP studies. There were both minor and major surgery types, 27 and 16 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent”, “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Previously Untreated and Minimally Treated Patients

Kogenate FS has been used in the treatment of bleeding episodes in pediatric previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe (< 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Kogenate FS for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated.

Table 12 Previously Untreated and Minimally Treated Patients (PUPs and MTPs) Clinical Trial Results

Clinical Parameters	Results
No. of Infusions of Kogenate FS Administered	9,419
No. of Exposure Days to Kogenate FS (median)	115 exposure days
No. of IU Administered	7.5 million IU
No. of Bleeds Treated with Kogenate FS	1,047
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS	one infusion 73.1% two infusions 15.0% total: 88.1%

 A total of 29 surgical procedures were performed in 23 patients during the PUPs and MTPs study. There were both minor and major surgery types, 23 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent,” “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Table 13 Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials

Type of Surgery	PTPs (N=31)		PUPs/MTPs (N=23)
	No. of Surgical Events	Outcome “Good” or “Excellent”	No. of Surgical Events	Outcome “Good” or “Excellent”
Minor Surgery (i.e., tooth extractions, catheter implantations, liver biopsies)	24	100%	21	100%
Major Surgery (i.e., joint replacements,

Kytril Injection

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Kytril Injection

Kytril Injection is a serotonin-3 (5-HT3) receptor antagonist indicated for:

• The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.


• The prevention and treatment of postoperative nausea and vomiting in adults. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided during the postoperative period, Kytril Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Kytril Injection Dosage and Administration

Prevention of Chemotherapy-Induced Nausea and Vomiting

Adult Patients

The recommended dosage for Kytril Injection is 10 mcg/kg administered intravenously within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given.

Infusion Preparation

Kytril Injection may be administered intravenously either undiluted over 30 seconds, or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.

Stability

Intravenous infusion of Kytril Injection should be prepared at the time of administration. However, Kytril Injection has been shown to be stable for at least 24 hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room temperature under normal lighting conditions.

As a general precaution, Kytril Injection should not be mixed in solution with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Pediatric Patients

The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see Clinical Studies (14)]. Pediatric patients under 2 years of age have not been studied.

Prevention and Treatment of Postoperative Nausea and Vomiting

Adult Patients

The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of KYTRIL, undiluted, administered intravenously over 30 seconds, before induction of anesthesia or immediately before reversal of anesthesia.

The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1 mg of KYTRIL, undiluted, administered intravenously over 30 seconds.

Dosage Forms and Strengths

Single-Use Vials for Injection: 1 mg/mL, 0.1 mg/mL

Multi-Use Vials for Injection: 4 mg/4 mL

Contraindications

Kytril Injection is contraindicated in patients with known hypersensitivity (eg. anaphylaxis, shortness of breath, hypotension, urticaria) to the drug or to any of its components.

Warnings and Precautions

Gastric or Intestinal Peristalsis

KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of KYTRIL in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

Cardiovascular Events

An adequate QT assessment has not been conducted, but QT prolongation has been reported with KYTRIL. Therefore, KYTRIL should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

Hypersensitivity Reactions

Hypersensitivity reactions (eg. anaphylaxis, shortness of breath, hypotension, urticaria) may occur in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists

Benzyl Alcohol

KYTRIL 1 mg/mL contains benzyl alcohol. Benzyl alcohol, a component of KYTRIL 1 mg/mL, has been associated with serious adverse reactions and death, particularly in neonates. The "gasping syndrome," characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Adverse Reactions

QT prolongation has been reported with KYTRIL [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Clinical Trials Experience

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

Chemotherapy-Induced Nausea and Vomiting

The following have been reported during controlled clinical trials or in the routine management of patients. The percentage figures are based on clinical trial experience only. Table 1 gives the comparative frequencies of the two most commonly reported adverse reactions (≥3%) in patients receiving Kytril Injection, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Kytril Injection administration. Reactions were generally recorded over seven days post-Kytril Injection administration.

Table 1 Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy

	Percent of Patients With Reaction
	Kytril Injection 40 mcg/kg (n=1268)	Comparator* (n=422)
* Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
Headache	14%	6%
Constipation	3%	3%

Additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea.

In over 3,000 patients receiving Kytril Injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in Table 1, were observed; attribution of many of these events to KYTRIL is uncertain.

Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and ALT (>2 times the upper limit of normal) following administration of Kytril Injection occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).

Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-sustained tachycardia, and ECG abnormalities have been observed rarely.

Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this syndrome.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative studies, fever occurred more frequently with Kytril Injection (8.6%) than with comparative drugs (3.4%, P<0.014), which usually included dexamethasone.

Postoperative Nausea and Vomiting

The adverse reactions listed in Table 2 were reported in ≥2% of adults receiving Kytril Injection 1 mg during controlled clinical trials.

Table 2 Adverse Reactions in Controlled Clinical Trials in Postoperative Nausea and Vomiting (Reported in ≥ 2% of Adults Receiving Kytril Injection 1 mg)

	Percent of Patients With Reaction
	Kytril Injection 1 mg (n=267)	Placebo (n=266)
Pain	10.1	8.3
Headache	8.6	7.1
Fever	7.9	4.5
Abdominal Pain	6.0	6.0
Hepatic Enzymes Increased	5.6	4.1
Dizziness	4.1	3.4
Diarrhea	3.4	1.1
Flatulence	3.0	3.0
Dyspepsia	3.0	1.9
Oliguria	2.2	1.5
Coughing	2.2	1.1

Additional adverse events reported in clinical trials were constipation, anemia, insomnia, bradycardia, leukocytosis, anxiety, hypotension, infection, hypertension, and urinary tract infection.

In a clinical study conducted in Japan, the types of adverse events differed notably from those reported above in Table 2. The adverse events in the Japanese study that occurred in ≥2% of patients and were more frequent with KYTRIL 1 mg than with placebo were: fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of KYTRIL. 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 KYTRIL exposure.

QT prolongation has been reported with KYTRIL [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Drug Interactions

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, Kytril Injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Kytril Injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by KYTRIL in vitro.

In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous KYTRIL. The clinical significance of this change is not known.

QT prolongation has been reported with KYTRIL. Use of KYTRIL in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day (35.4 mg/m2/day, 96 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Benzyl alcohol may cross the placenta. Kytril Injection 1 mg/mL is preserved with benzyl alcohol and should be used in pregnancy only if the benefit outweighs the potential risk.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Kytril Injection is administered to a nursing woman.

Pediatric Use

Benzyl alcohol, a component of KYTRIL 1 mg/mL, has been associated with serious adverse reactions and death, particularly in neonates [see Warnings and Precautions (5.4)].

Chemotherapy-Induced Nausea and Vomiting

[See Dosage and Administration (2)] for use in chemotherapy-induced nausea and vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric patients under 2 years of age have not been established.

Postoperative Nausea and Vomiting

Safety and efficacy have not been established in pediatric patients for the prevention of postoperative nausea and vomiting (PONV). Granisetron has been evaluated in a pediatric patient clinical trial for use in the prevention of PONV. Due to the lack of efficacy and the QT prolongation observed in this trial, use of granisetron for the prevention of PONV in children is not recommended. The trial was a prospective, multicenter, randomized, double-blind, parallel-group trial that evaluated 157 children aged 2 to 16 years who were undergoing elective surgery for tonsillectomy or adenotonsillectomy. The purpose of the trial was to assess two dose levels (20 mcg/kg and 40 mcg/kg) of intravenous granisetron in the prevention of PONV. There was no active comparator or placebo. The primary endpoint was total control of nausea and vomiting (defined as no nausea, vomiting/retching, or use of rescue medication) in the 24 hours following surgery. Efficacy was not established due to lack of a dose response.

The trial also included standard 12 lead ECGs performed pre-dose and after the induction of anesthesia. ECGs were repeated at the end of surgery after the administration of granisetron and just prior to reversal of anesthesia. QT prolongation was seen at both dose levels. Five patients in this trial experienced an increase of ≥ 60 msec in QTcF. In addition, there were two patients whose QTcF was ≥ 500 msec. Interpretation of the QTcF prolongation was confounded by multiple factors, including the use of concomitant medication and the lack of either a placebo or active control. A thorough QT trial in adults has not been performed.

Other adverse events that occurred in the study included: vomiting (5-8%), post-procedural hemorrhage (3-5%), and dehydration (0-5%).

Pediatric patients under 2 years of age have not been studied.

Geriatric Use

During chemotherapy clinical trials, 713 patients 65 years of age or older received Kytril Injection. The safety and effectiveness were similar in patients of various ages.

During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or older, of which 47 were 75 years of age or older, received Kytril Injection. Clinical studies of Kytril Injection did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Overdosage

There is no specific antidote for Kytril Injection overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

Kytril Injection Description

KYTRIL (granisetron hydrochloride) Injection is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its chemical structure is:

granisetron hydrochloride

Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C. Kytril Injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration.

KYTRIL 1 mg/mL is available in 1 mL single-use and 4 mL multi-use vials. KYTRIL 0.1 mg/mL is available in a 1 mL single-use vial.

1 mg/mL: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg, as a preservative. The solution's pH ranges from 4.0 to 6.0.

0.1 mg/mL: Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to granisetron, 0.1 mg; sodium chloride, 9 mg; citric acid, 2 mg. Contains no preservative. The solution's pH ranges from 4.0 to 6.0.

Kytril Injection - Clinical Pharmacology

Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.

Kytril Injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal volunteers.

Pharmacokinetics

Chemotherapy-Induced Nausea and Vomiting

In adult cancer patients undergoing chemotherapy and in volunteers, mean pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of Kytril Injection are shown in Table 3.

Table 3 Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of Kytril Injection

	Peak Plasma Concentration (ng/mL)	Terminal Phase Plasma Half-Life (h)	Total Clearance (L/h/kg)	Volume of Distribution (L/kg)
* 5-minute infusion. † 3-minute infusion.
Cancer Patients
Mean	63.8*	8.95*	0.38*	3.07*
Range	18.0 to 176	0.90 to 31.1	0.14 to 1.54	0.85 to 10.4
Volunteers
21 to 42 years
Mean	64.3†	4.91†	0.79†	3.04†
Range	11.2 to 182	0.88 to 15.2	0.20 to 2.56	1.68 to 6.13
65 to 81 years
Mean	57.0†	7.69†	0.44†	3.97†
Range	14.6 to 153	2.65 to 17.7	0.17 to 1.06	1.75 to 7.01

Distribution

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.

Elimination

Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.

Subpopulations

Gender

There was high inter- and intra-subject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher Cmax generally.

Elderly

The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of Kytril Injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly patients (see Table 3).

Pediatric Patients

A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of Kytril Injection, showed that volume of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients.

Renal Failure Patients

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of Kytril Injection.

Hepatically Impaired Patients

A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic functional impairment is not necessary.

Postoperative Nausea and Vomiting

In adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of Kytril Injection administered intravenously over 30 seconds are shown in Table 4.

Table 4 Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single Intravenous 1 mg Dose of Kytril Injection

	Terminal Phase Plasma Half-Life (h)	Total Clearance (L/h/kg)	Volume of Distribution (L/kg)
Mean	8.63	0.28	2.42
Range	1.77 to 17.73	0.07 to 0.71	0.71 to 4.13

The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, 16 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Kytril Injection should be prescribed only at the dose and for the indication recommended [see Indications and Usage (1) and Dosage and Administration (2)].

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Clinical Studies

Chemotherapy-Induced Nausea and Vomiting

Single-Day Chemotherapy

Cisplatin-Based Chemotherapy

In a double-blind, placebo-controlled study in 28 cancer patients, Kytril Injection, administered as a single intravenous infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin chemotherapy (see Table 5).

Table 5 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day Cisplatin Therapy*

	Kytril Injection	Placebo	P-Value
* Cisplatin administration began within 10 minutes of Kytril Injection infusion and continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the Kytril Injection group and 80 mg/m2 in the placebo group. † No vomiting and no moderate or severe nausea.
Number of Patients	14	14
Response Over 24 Hours
Complete Response†	93%	7%	<0.001
No Vomiting	93%	14%	<0.001
No More Than Mild Nausea	93%	7%	<0.001

Kytril Injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. Kytril Injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg (see Table 6).

Table 6 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose Cisplatin Therapy*

	Kytril Injection (mcg/kg)			P-Value (vs. 2 mcg/kg)
	2	10	40	10	40
* Cisplatin administration began within 10 minutes of Kytril Injection infusion and continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2. † No vomiting and no moderate or severe nausea.
Number of Patients	52	52	53
Response Over 24 Hours
Complete Response†	31%	62%	68%	<0.002	<0.001
No Vomiting	38%	65%	74%	<0.001	<0.001
No More Than Mild Nausea	58%	75%	79%	NS	0.007

Kytril Injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin dose. Response rates of patients for both cisplatin strata are given in Table 7.

Table 7 Prevention of Chemotherapy-Induced Nausea and Vomiting — Single-Day High-Dose and Low-Dose Cisplatin Therapy*

	Kytril Injection (mcg/kg)				P-Value (vs. 5 mcg/kg)
	5	10	20	40	10	20	40
* Cisplatin administration began within 10 minutes of Kytril Injection infusion and continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and high strata. † No vomiting and no use of rescue antiemetic.
High-Dose Cisplatin
Number of Patients	40	49	48	47
Response Over 24 Hours
Complete Response†	18%	41%	40%	47%	0.018	0.025	0.004
No Vomiting	28%	47%	44%	53%	NS	NS	0.016
No Nausea	15%	35%	38%	43%	0.036	0.019	0.005
Low-Dose Cisplatin
Number of Patients	42	41	40	46
Response Over 24 Hours
Complete Response†	29%	56%	58%	41%	0.012	0.009	NS
No Vomiting	36%	63%	65%	43%	0.012	0.008	NS
No Nausea	29%	56%	38%	33%	0.012	NS	NS

For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher doses.

Moderately Emetogenic Chemotherapy

Kytril Injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide >600 mg/m2. Kytril Injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see Table 8).

Table 8 Prevention of Chemotherapy-Induced Nausea and Vomiting—Single-Day Moderately Emetogenic Chemotherapy

	Kytril Injection	Chlorpromazine*	P-Value
* Patients also received dexamethasone, 12 mg. † No vomiting and no moderate or severe nausea.
Number of Patients	133	133
Response Over 24 Hours
Complete Response†	68%	47%	<0.001
No Vomiting	73%	53%	<0.001
No More Than Mild Nausea	77%	59%	<0.001

In other studies of moderately emetogenic chemotherapy, no significant differe

Klor-Con M10 Controlled-Release Tablets

Pronunciation: po-TAS-ee-um KLOR-ide
Generic Name: Potassium Chloride
Brand Name: Examples include K-Dur and Klor-Con M10

Klor-Con M10 Controlled-Release Tablets are used for:

Preventing or treating low blood potassium levels in certain patients. Low blood potassium levels may be caused by certain diseases, severe or prolonged episodes of vomiting or diarrhea, certain medicines (eg, corticosteroids, digitalis, diuretics), surgery, or other conditions. It may also be used for other conditions as determined by your doctor.

Klor-Con M10 Controlled-Release Tablets are an electrolyte. It works by providing potassium when you have low levels of potassium in your blood.

Do NOT use Klor-Con M10 Controlled-Release Tablets if:

• you are allergic to any ingredient in Klor-Con M10 Controlled-Release Tablets


• you have high blood potassium levels, severe kidney problems, narrowing of the esophagus because of an enlarged heart, or a blockage, slowing, or paralysis of the esophagus, stomach, or intestines


• you are taking an aldosterone blocker (eg, eplerenone), an anticholinergic (eg, methscopolamine), or a potassium-sparing diuretic (eg, spironolactone, triamterene)

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

Before using Klor-Con M10 Controlled-Release Tablets:

Some medical conditions may interact with Klor-Con M10 Controlled-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

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


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


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


• if you have adrenal gland, esophagus, kidney, or potassium excretion problems; diabetes; diarrhea; extensive tissue injury (eg, severe burns); heart problems (eg, irregular heartbeat, heart failure, mitral valve replacement); heat cramps; high blood acid levels; high blood pressure; muscle weakness or paralysis; or scleroderma; or if you are dehydrated


• if you are confined to a bed or chair

Some MEDICINES MAY INTERACT with Klor-Con M10 Controlled-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Aldosterone blockers (eg, eplerenone), angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril), nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), or potassium-sparing diuretics (eg, spironolactone, triamterene) because the risk of high blood potassium levels may be increased


• Anticholinergics (eg, methscopolamine) because the risk of esophagus, intestinal, or stomach problems may be increased


• Digoxin because the risk of its side effects may be increased by Klor-Con M10 Controlled-Release Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Klor-Con M10 Controlled-Release Tablets 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 Klor-Con M10 Controlled-Release Tablets:

Use Klor-Con M10 Controlled-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Klor-Con M10 Controlled-Release Tablets by mouth with food or after a meal.


• Take Klor-Con M10 Controlled-Release Tablets with a full glass of water (8 oz/240 mL). Do not lie down for 30 minutes after taking Klor-Con M10 Controlled-Release Tablets.


• Swallow Klor-Con M10 Controlled-Release Tablets whole. Do not crush, chew, or suck on the tablet before swallowing.


• If you have trouble swallowing the tablet whole, you may break the tablet in half and swallow each half separately with a glass of water. You may also dissolve the tablet in half a glass (4 oz/120 mL) of water. Let the tablet dissolve for 2 minutes, then stir well for half a minute. Swirl and drink all the liquid right away. Add 1 oz/30 mL of water to the glass, swirl, and drink; repeat this 1 more time to ensure you have taken all of the medicine.


• Throw away any unused mixture. Do not store the mixture for future use.


• If you miss a dose of Klor-Con M10 Controlled-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Klor-Con M10 Controlled-Release Tablets.

Important safety information:

• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• If you have trouble swallowing Klor-Con M10 Controlled-Release Tablets, or if it seems to stick to your throat, check with your doctor.


• Lab tests, including blood potassium, kidney function, and electrocardiograms (ECG), may be performed while you use Klor-Con M10 Controlled-Release Tablets. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Klor-Con M10 Controlled-Release Tablets with caution in the ELDERLY; they may be more sensitive to its effects.


• Klor-Con M10 Controlled-Release Tablets should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Klor-Con M10 Controlled-Release Tablets while you are pregnant. Klor-Con M10 Controlled-Release Tablets are found in breast milk. If you are or will be breast-feeding while you use Klor-Con M10 Controlled-Release Tablets, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Klor-Con M10 Controlled-Release Tablets:

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:

Diarrhea; gas; nausea; stomach discomfort; vomiting.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; chest pain; irregular heartbeat; listlessness; numbness or tingling in your skin, lips, hands, or feet; severe nausea or vomiting; stomach pain or swelling; unusual confusion or anxiety; unusual muscle weakness or paralysis; vomit that looks like coffee grounds; weak or heavy legs.

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: Klor-Con M10 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. Symptoms may include chest pain; fast, slow, or irregular heartbeat; limp muscles; listlessness; muscle weakness or paralysis; slow or difficult breathing.

Proper storage of Klor-Con M10 Controlled-Release Tablets:

Store Klor-Con M10 Controlled-Release Tablets at 77 degrees F (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 Klor-Con M10 Controlled-Release Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Klor-Con M10 Controlled-Release Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Klor-Con M10 Controlled-Release Tablets are 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 Klor-Con M10 Controlled-Release Tablets. 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 Klor-Con M10 resources

• Klor-Con M10 Side Effects (in more detail)
• Klor-Con M10 Use in Pregnancy & Breastfeeding
• Drug Images
• Klor-Con M10 Drug Interactions
• Klor-Con M10 Support Group
• 0 Reviews for Klor-Con M10 - Add your own review/rating

Compare Klor-Con M10 with other medications

• Hypokalemia
• Prevention of Hypokalemia

KneeRelief

Generic Name: acetaminophen, caffeine, and magnesium salicylate (ah seet oh MIN oh fen, KAF een, mag NEEZ ee um sa LIS il ate)

Brand Names: KneeRelief

What is KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

Acetaminophen is a pain reliever and a fever reducer.

Caffeine is used in this product to increase the pain relieving effects of acetaminophen.

Magnesium salicylate is used to reduce pain, inflammation, and fever.

The combination of acetaminophen, caffeine, and magnesium salicylate is used to treat pain and swelling from conditions such as muscle aches, arthritis, and joint soreness.

Acetaminophen, caffeine, and magnesium salicylate may also be used for purposes not listed in this medication guide.

What is the most important information I should know about KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

Magnesium salicylate should not be given to a child or teenager who has a fever, especially if the child also has flu symptoms or chicken pox. Salicylates can cause a serious and sometimes fatal condition called Reye's syndrome in children. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen. Ask a doctor or pharmacist before using any other pain, cold, allergy, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

Stop taking this medication and call your doctor if you have a fever lasting longer than 3 days, or pain lasting longer than 10 days.

What should I discuss with my healthcare provider before taking KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

You should not use this medication if you are allergic to acetaminophen, caffeine, or magnesium salicylate. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• 
  

  a stomach ulcer or bleeding;

  
  


• liver disease;


• kidney disease;


• 
  

  gout;

  
  


• 
  

  a bleeding or blood clotting disorder, such as hemophilia;

  
  


• 
  

  heart disease or congestive heart failure; or

  
  


• 
  

  high blood pressure (hypertension).

  
  

FDA pregnancy category C. It is not known whether acetaminophen, caffeine, and magnesium salicylate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Acetaminophen, caffeine, and magnesium salicylate can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Magnesium salicylate should not be given to a child or teenager who has a fever, especially if the child also has flu symptoms or chicken pox. Salicylates can cause a serious and sometimes fatal condition called Reye's syndrome in children.

How should I take KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

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

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Stop taking this medication and call your doctor if you have a fever lasting longer than 3 days, or pain lasting longer than 10 days.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using acetaminophen, caffeine, and magnesium salicylate. If you need surgery, tell the surgeon ahead of time that you are using acetaminophen, caffeine, and magnesium salicylate. You may need to stop using the medicine for a short time. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Since this medication is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, 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 or call the Poison Help line at 1-800-222-1222. An overdose of acetaminophen can damage your liver or cause death.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms also may include ringing in your ears, headache, confusion, agitation, restless feeling, insomnia, hallucinations, low fever, loss of appetite, seizures, or coma.

What should I avoid while taking KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen. Ask a doctor or pharmacist before using any other pain, cold, allergy, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

Many medicines available over the counter also contain caffeine, salicylates, or similar medicines (such as aspirin, ibuprofen, ketoprofen, or naproxen). Ask your doctor before taking any other medication for pain, arthritis, fever, or swelling.

KneeRelief (acetaminophen, caffeine, and magnesium salicylate) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop taking this medicine and call your doctor at once if you have a serious side effect such as: Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  black, bloody, or tarry stools;

  
  


• 
  

  coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  easy bruising or bleeding;

  
  


• 
  

  agitation, confusion, or hallucinations; or

  
  


• 
  

  seizure (convulsions).

  
  

Less serious side effects may include:

• 
  

  mild nausea, vomiting, indigestion, or upset stomach;

  
  


• 
  

  ringing in your ears; or

  
  


• 
  

  trouble sleeping (insomnia).

  
  

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 KneeRelief (acetaminophen, caffeine, and magnesium salicylate)?

Ask a doctor or pharmacist if it is safe for you to use acetaminophen, caffeine, and magnesium salicylate if you are also using any of the following drugs:

• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven), heparin, enoxaparin (Lovenox), dalteparin (Fragmin), or tinzaparin (Innohep);

  
  


• 
  

  choline and magnesium salicylate (Trilisate, Tricosal), or salsalate (Disalcid);

  
  


• 
  

  salicylates such as aspirin, Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others;

  
  


• 
  

  medication used to prevent blood clots, such as alteplase (Activase), dipyridamole (Persantine), ticlopidine (Ticlid), and urokinase (Abbokinase); or

  
  


• 
  

  aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.

  
  

This list is not complete and other drugs may interact with acetaminophen, caffeine, and magnesium salicylate. 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 KneeRelief resources

• KneeRelief Drug Interactions
• KneeRelief Support Group
• 2 Reviews for KneeRelief - Add your own review/rating

Compare KneeRelief with other medications

• Muscle Pain

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, caffeine, and magnesium salicylate.