Fragmin

dalteparin sodium

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: SPINAL/EPIDURAL HEMATOMAS

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• Use of indwelling epidural catheters


• Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.


• A history of traumatic or repeated epidural or spinal punctures


• A history of spinal deformity or spinal surgery

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Indications and Usage for Fragmin

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Fragmin® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies (14.1)].

Prophylaxis of Deep Vein Thrombosis

Fragmin is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

• In patients undergoing hip replacement surgery [see Clinical Studies (14.2)];


• In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3)];


• In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4)].

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

Fragmin is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer In these patients, the Fragmin therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5)].

Limitations of Use

Fragmin is not indicated for the acute treatment of VTE.

Fragmin Dosage and Administration

Fragmin is administered by subcutaneous injection. It must not be administered by intramuscular injection.

Fragmin Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Fragmin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Fragmin. [See Warnings and Precautions (5)].

Adult Dosage

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Fragmin Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.

Table 1 lists the volume of Fragmin, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

Table 1
Volume of Fragmin to be Administered by Patient Weight, Based on 9.5 mL Vial (10,000 IU/mL)
Patient weight (lb)	< 110	110 to 131	132 to 153	154 to 175	176 to 197	≥ 198
Patient weight (kg)	< 50	50 to 59	60 to 69	70 to 79	80 to 89	≥ 90
Volume of Fragmin (mL)	0.55	0.65	0.75	0.90	1.0	1.0

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery: Table 2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with Fragmin have been well tolerated in clinical trials.

1  Or later, if hemostasis has not been achieved. 2  Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively. 3  Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly. 4  Allow approximately 24 hours between doses.
Table 2
Dosing Options for Patients Undergoing Hip Replacement Surgery
Timing of First Dose of Fragmin	Dose of Fragmin to be Given Subcutaneously
	10 to 14 Hours Before Surgery	Within 2 Hours Before Surgery	4 to 8 Hours After Surgery1	Postoperative Period2
Postoperative Start	---	---	2500 IU3	5000 IU once daily
Preoperative Start - Day of Surgery	---	2500 IU	2500 IU3	5000 IU once daily
Preoperative Start - Evening Before Surgery4	5000 IU	---	5000 IU	5000 IU once daily

Abdominal Surgery: In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of Fragmin is 2500 IU administered by subcutaneous injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.

In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of Fragmin is 5000 IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of Fragmin can be administered subcutaneously 1 to 2 hours before surgery followed by 2500 IU subcutaneously 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.

Medical Patients During Acute Illness: In medical patients with severely restricted mobility during acute illness, the recommended dose of Fragmin is 5000 IU administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer: In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of Fragmin is as follows: for the first 30 days of treatment administer Fragmin 200 IU/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000 IU. Table 3 lists the dose of Fragmin to be administered once daily during the first month for a range of patient weights.

Month 1

Table 3
Dose of Fragmin to be Administered Subcutaneously by Patient Weight during the First Month
Body Weight (lbs)	Body Weight (kg)	Fragmin Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	10,000
125 to 150	57 to 68	12,500
151 to 181	69 to 82	15,000
182 to 216	83 to 98	18,000
≥ 217	≥ 99	18,000

Months 2 to 6

Administer Fragmin at a dose of approximately 150 IU/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 4 lists the dose of Fragmin to be administered once daily for a range of patient weights during months 2-6.

Table 4
Dose of Fragmin to be Administered Subcutaneously by Patient Weight during Months 2-6
Body Weight (lbs)	Body Weight (kg)	Fragmin Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	7,500
125 to 150	57 to 68	10,000
151 to 181	69 to 82	12,500
182 to 216	83 to 98	15,000
≥ 217	≥ 99	18,000

Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE [see Warnings and Precaution (5) and Adverse Reactions (6.1)].

Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving Fragmin who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of Fragmin by 2,500 IU until the platelet count recovers to ≥ 100,000/mm3. In patients receiving Fragmin who experience platelet counts < 50,000/mm3, discontinue Fragmin until the platelet count recovers above 50,000/mm3.

Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate Fragmin dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after Fragmin dosing and only after the patient has received 3-4 doses.

Administration

Subcutaneous injection technique: Patients should be sitting or lying down and Fragmin administered by deep subcutaneous injection. Fragmin may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.

Inspect Fragmin prefilled syringes and vials visually for particulate matter and discoloration prior to administration

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Dosage Forms and Strengths

2,500 IU / 0.2 mL single-dose prefilled syringe

5,000 IU / 0.2 mL single-dose prefilled syringe

7,500 IU / 0.3 mL single-dose prefilled syringe

10,000 IU / 0.4 mL single-dose prefilled syringe

10,000 IU / 1 mL single-dose graduated syringe

12,500 IU / 0.5 mL single-dose prefilled syringe

15,000 IU / 0.6 mL single-dose prefilled syringe

18,000 IU / 0.72 mL single-dose prefilled syringe

95,000 IU / 3.8 mL multiple-dose vial

95,000 IU / 9.5 mL multiple-dose vial

Contraindications

• Active major bleeding


• History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.


• Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.2)]


• In patients undergoing Epidural/Neuraxial anesthesia, do not administer Fragmin [See Boxed Warning];
  
  • As a treatment for unstable angina and non_q wave MI
  
  
  • For prolonged VTE prophylaxis.
  
  


• Hypersensitivity to heparin or pork products

Warnings and Precautions

Increased Risk of Hemorrhage

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity , [see Boxed Warning and Adverse Reactions (6.2) and Drug Interactions (7)].

Use Fragmin with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Fragmin may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with Fragmin.

Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of Fragmin. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed.[See Contraindications (4)] Closely monitor thrombocytopenia of any degree.

In Fragmin clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm3 occurred in < 1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the Fragmin treatment arm, platelet counts of < 100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the Fragmin arm and 8.1% of patients in the OAC arm. Fragmin dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.

Benzyl Alcohol

Each multiple-dose vial of Fragmin contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering Fragmin preserved with benzyl alcohol to pregnant women. If anticoagulation with Fragmin is needed during pregnancy, use preservative-free formulations, where possible. [See Use in Specific Populations (8.1)].

Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with Fragmin. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Fragmin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Fragmin. Anti-Factor Xa may be used to monitor the anticoagulant effect of Fragmin, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during Fragmin therapy.

Adverse Reactions

Clinical Trials Experience

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

Hemorrhage

The incidence of hemorrhagic complications during treatment with Fragmin Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 5 summarizes major bleeding reactions that occurred with Fragmin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

1  Treatment was administered for 5 to 8 days. 2  Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days. 3  Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently. 4  Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding.
Table 5
Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication	Dosing Regimen
Unstable Angina and Non-Q-Wave MI	Fragmin 120 IU/kg/12 hr subcutaneous1 n (%)	Heparin2 intravenous and subcutaneous2 n (%)	Placebo every 12 hr subcutaneous n (%)
Major Bleeding Reactions3,4	15/1497 (1.0)	7/731 (1.0)	4/760 (0.5)

Hip Replacement Surgery

Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with Fragmin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

1  Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5. 2  Includes three treated patients who did not undergo a surgical procedure. 3  A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥ 2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 4  Includes two treated patients who did not undergo a surgical procedure. 5  Occurred at a rate of at least 2% in the group treated with Fragmin 5000 IU once daily.
Table 6
Bleeding Reactions Following Hip Replacement Surgery
Indication	Fragmin vs Warfarin Sodium		Fragmin vs Heparin
	Dosing Regimen		Dosing Regimen
Hip Replacement Surgery	Fragmin2 5000 IU once daily subcutaneous n (%)	Warfarin Sodium1 oral n (%)	Fragmin4 5000 IU once daily subcutaneous n (%)	Heparin 5000 U three times a day subcutaneous n (%)
Major Bleeding Reactions3	7/274 (2.6)	1/279 (0.4)	0	3/69 (4.3)
Other Bleeding Reactions5 Hematuria	8/274 (2.9)	5/279 (1.8)	0	0
Wound Hematoma	6/274 (2.2)	0	0	0
Injection Site Hematoma	3/274 (1.1)	NA	2/69 (2.9)	7/69 (10.1)

Six of the patients treated with Fragmin experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.

In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started Fragmin before surgery; 2.5% (12/487) for patients who started Fragmin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.

Abdominal Surgery

Table 7 summarizes bleeding reactions that occurred in clinical trials which studied Fragmin 2500 and 5000 IU administered once daily to abdominal surgery patients.

Table 7
Bleeding Reactions Following Abdominal Surgery
Indication	Fragmin vs Placebo		Fragmin vs Fragmin
	Dosing Regimen		Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)	Fragmin 2500 IU once daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)
Postoperative Transfusions	14/182 (7.7)	13/182 (7.1)	89/1025 (8.7)	125/1033 (12.1)
Wound Hematoma	2/79 (2.5)	2/77 (2.6)	1/1030 (0.1)	4/1039 (0.4)
Reoperation Due to Bleeding	1/79 (1.3)	1/78 (1.3)	2/1030 (0.2)	13/1038 (1.3)
Injection Site Hematoma	8/172 (4.7)	2/174 (1.1)	36/1026 (3.5)	57/1035 (5.5)
Indication	Fragmin vs Heparin
	Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)
Postoperative Transfusions	26/459 (5.7)	36/454 (7.9)	81/508 (15.9)	63/498 (12.7)
Wound Hematoma	16/467 (3.4)	18/467 (3.9)	12/508 (2.4)	6/498 (1.2)
Reoperation Due to Bleeding	2/392 (0.5)	3/392 (0.8)	4/508 (0.8)	2/498 (0.4)
Injection Site Hematoma	1/466 (0.2)	5/464 (1.1)	36/506 (7.1)	47/493 (9.5)

In a trial comparing Fragmin 5000 IU once daily to Fragmin 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Fragmin 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for Fragmin and Heparin (n.s.).

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

1  A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.
Table 8
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication	Dosing Regimen
Medical Patients with Severely Restricted Mobility	Fragmin 5000 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)
Major Bleeding Reactions1 at Day 14	8/1848 (0.4)	0/1833 (0)
Major Bleeding Reactions1 at Day 21	9/1848 (0.5)	3/1833 (0.2)

Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Fragmin and one in the group receiving placebo).

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.

At the end of the six-month study, a total of 46 (13.6%) patients in the Fragmin arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Fragmin arm at Day 71) was fatal.

1  Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.
Table 9
Bleeding Reactions (Major and Any) (As treated population)1
Study period	Fragmin 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months			OAC Fragmin 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)
	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)
Total during study	338	19 (5.6)	46 (13.6)	335	12 (3.6)	62 (18.5)
Week 1	338	4 (1.2)	15 (4.4)	335	4 (1.2)	12 (3.6)
Weeks 2-4	332	9 (2.7)	17 (5.1)	321	1 (0.3)	12 (3.7)
Weeks 5-28	297	9 (3.0)	26 (8.8)	267	8 (3.0)	40 (15.0)

Thrombocytopenia

[See Warnings and Precautions (5.2)]

Elevations of Serum Transaminases

In Fragmin clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Fragmin.

In the Fragmin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Fragmin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.

Other

Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.

Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with Fragmin and reported at a rate of at least 2% in the group treated with Fragmin, was reported in 4.5% of patients treated with Fragmin 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with Fragmin 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Fragmin. 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.

Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete). [see Boxed Warning]

Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.

Drug Interactions

Use Fragmin with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding [see Warning and Precautions (5)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Fragmin use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m2) (rats) and 4800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of Fragmin contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3)].

Nursing Mothers

Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when Fragmin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in clinical studies of Fragmin, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of Fragmin between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those predisposed to decreased renal function [see Warnings and Precautions (5) and Clinical Pharmacology (12)].

Overdosage

An excessive dosage of Fragmin Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of Fragmin given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of Fragmin may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).

Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.

Fragmin Description

Fragmin Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.

Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5. [See Dosage and Administration (2) and How Supplied (16)]

Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. The molecular weight distribution is:

    < 3000 daltons    3.0-15%

    3000 to 8000 daltons    65.0-78.0%

    > 8000 daltons    14.0-26.0%

STRUCTURAL FORMULA

Fragmin - Clinical Pharmacol

metaproterenol Inhalation

met-a-proe-TER-e-nol

Commonly used brand name(s)

In the U.S.

• Alupent

Available Dosage Forms:

• Solution


• Aerosol Powder


• Aerosol Liquid

Therapeutic Class: Bronchodilator

Pharmacologic Class: Beta-2 Adrenergic Agonist

Uses For metaproterenol

Metaproterenol is used to treat asthma and bronchospasm in patients with bronchitis, emphysema, and other lung diseases.

Metaproterenol belongs to the family of medicines known as adrenergic bronchodilators. Adrenergic bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. They relieve cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

metaproterenol is available only with your doctor's prescription.

Before Using metaproterenol

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 metaproterenol, the following should be considered:

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of metaproterenol inhalation aerosol in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of metaproterenol inhalation aerosol in geriatric patients.

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 metaproterenol, 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 metaproterenol 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.

• Acebutolol


• Alprenolol


• Arotinolol


• Atenolol


• Befunolol


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Bucindolol


• Bupranolol


• Carteolol


• Carvedilol


• Celiprolol


• Dilevalol


• Esmolol


• Labetalol


• Landiolol


• Levobetaxolol


• Levobunolol


• Mepindolol


• Metipranolol


• Metoprolol


• Nadolol


• Nebivolol


• Nipradilol


• Oxprenolol


• Penbutolol


• Pindolol


• Propranolol


• Sotalol


• Talinolol


• Tertatolol


• Timolol

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Diabetes or


• Heart or blood vessel disease or


• Hypertension (high blood pressure) or


• Hyperthyroidism (overactive thyroid) or


• Seizures—Use with caution. May make these conditions worse.

• Heart rhythm problems (e.g., arrhythmia) or


• Tachycardia (fast or rapid heartbeat)—Should not be used in patients with these conditions.

Proper Use of metaproterenol

Use metaproterenol only as directed by your doctor. Do not use more of it and do not use it more often than your doctor ordered. Also, do not stop using metaproterenol or any asthma medicine without telling your doctor. To do so may increase the chance for breathing problems.

Alupent(R) inhalation aerosol is used with a special inhaler that comes with patient instructions. Read the directions carefully before using metaproterenol. If you or your child do not understand the directions or are not sure how to use the inhaler, ask your doctor to show you what to do. Also, ask your doctor to check you or your child on a regular basis to make sure you are using it properly.

To use the inhaler:

• Insert the metal canister firmly and fully into the clear end of the mouthpiece.


• This mouthpiece should not be used with other inhaled medicines.


• Remove the cap and look at the mouthpiece to make sure it is clean.


• Shake the inhaler well before using.


• To inhale metaproterenol, first breathe out fully. Try to get as much air out of the lungs as possible.


• Put the mouthpiece just in front of your mouth with the canister upright.


• Open your mouth and breathe in slowly and deeply (like yawning). At the same time, firmly press down once on the top of the canister.


• Hold your breath for a few seconds, then breathe out slowly.


• If you are supposed to use more than one puff, wait at least 2 minutes before inhaling the second puff. Repeat these steps for the second puff, starting with shaking the inhaler.


• When you have finished all of your doses, rinse your mouth with water and spit the water out.


• Clean the inhaler mouthpiece every day with hot water. Dry it thoroughly before use.

Dosing

The dose of metaproterenol 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 metaproterenol. 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 asthma and bronchospasm:
  
  • For inhalation dosage form (aerosol):
    
    • Adults and teenagers—Two to three puffs every 3 to 4 hours as needed. However, the total dose is usually not more than 12 puffs per day.
    
    
    • Children younger than 12 years of age—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of metaproterenol, 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 canister at room temperature, away from heat and direct light. Do not freeze. Do not keep metaproterenol inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using metaproterenol

It is very important that your doctor check your progress or your child's progress at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

metaproterenol may cause paradoxical bronchospasm, which may be life-threatening. Check with your doctor right away if you or your child are having a cough, difficulty with breathing, shortness of breath, or wheezing after using the medicine.

Check with your doctor at once if you or your child continue to have breathing problems after using a dose of metaproterenol or if your condition gets worse.

Do not change your dose or stop using metaproterenol without asking your doctor first.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, and herbal or vitamin supplements.

metaproterenol Side Effects

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

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

More common

• Fast, pounding, or irregular heartbeat or pulse

Less common

• Shakiness in the legs, arms, hands, or feet


• trembling or shaking of the hands or feet


• worsening of asthma

Rare

• Blurred vision


• chest pain


• chills


• cough


• diarrhea


• dizziness


• fainting


• fever


• general feeling of discomfort or illness


• headache


• increased sweating


• joint pain


• loss of appetite


• muscle aches and pains


• nausea


• nervousness


• pounding in the ears


• puffiness of the face and fingers


• runny nose


• shivering


• slow or fast heartbeat


• sore throat


• sweating


• swelling


• trouble sleeping


• unusual tiredness or weakness


• vomiting

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

Symptoms of overdose

• Arm, back, or jaw pain


• chest discomfort


• chest tightness or heaviness


• confusion


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


• dry mouth


• general feeling of discomfort or illness


• shortness of breath


• sleeplessness


• unable to sleep

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:

Less common

• Abdominal or stomach pain

Rare

• Bad, unusual, or unpleasant (after) taste


• change in appetite


• drowsiness


• dry mouth or throat


• itching skin


• pain


• raised red swellings on the skin, lips, tongue, or in the throat


• tightening of the muscles


• weakness

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: metaproterenol Inhalation 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.

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MyOxin

chloroxylenol, benzocaine, and hydrocortisone acetate

Dosage Form: otic suspension
MyOxin™

otic suspension

Chloroxylenol 1 mg

Benzocaine 15 mg

Hydrocortisone Acetate 10 mg

Rx Only

MyOxin Description

Each 1 mL for otic administration contains:

Chloroxylenol	1 mg
Benzocaine	15 mg
Hydrocortisone Acetate	10 mg

INACTIVE INGREDIENTS: PEG-12 Glyceryl Dimyristate, Sodium Hydroxide, PEG-40 HCO, Purified Water, Acrylates/C10-30 Alkyl Acrylate Crosspolymer, Xanthan Gum, Potassium Sorbate, Isopropyl Alcohol.

CLINICAL PHARMACOLOGY1

MyOxin is effective both as an antibacterial and antifungal agent. The unique delivery system provides a suspension having an acid pH and a low surface tension, exerting a drying effect and allowing the medication to spread quickly to all contiguous surfaces, softening and reducing accumulated cerumen. Chloroxylenol is a halogenated phenol; non-toxic, non-corrosive, non-staining with high phenol coefficient. It may be applied directly to a wound and shows no chemical reactivity toward blood. MyOxin which contains hydrocortisone acetate is indicated when otitis is complicated by inflammation or to control itching. Benzocaine is a topical anesthetic with a low index of sensitization and toxicity.

1

van Asperen IA, de Rover CM, Schijven JF, et al. Risk of otitis externa after swimming in recreational fresh water lakes containing Pseudomonas aeruginosa. BMJ.1995;311:1407-1410. Sander R.Otitis Externa: A Practical Guide to Treatment and Prevention. Available at http://www..aafp.org/afp/20010301/927.html. Accessed 4/9/09.

Indications and Usage for MyOxin

For the treatment of superficial infections of the external auditory canal complicated by inflammation caused by organisms susceptible to the action of the antimicrobial. May also be used to control itching in the auditory canal.

Contraindications

Topical steroids are contraindicated in varicella, vaccinia and in patients sensitive to any of the components of this preparation. The preparation is not to be used for ophthalmic use and should not be applied in the external auditory canal of patients with perforated eardrums.

Warnings

This preparation is not intended for ophthalmic or oral use. If accidental ingestion occurs, seek professional help. If irritation or sensitization occurs, promptly discontinue use of this preparation and institute other measures.

Precautions

General

If a favorable response does not occur promptly, discontinue the use of this preparation until the infection is controlled by other appropriate measures. Although systemic side effects are not common with topical corticosteroids, the possibility of occurrence must be kept in mind, particularly when used for an extended period of time.

USAGE IN PREGNANCY

The safety of topical steroid preparations during pregnancy has not been established. Therefore, they should not be used on pregnant patients.

Adverse Reactions

The following adverse reactions with topical corticosteroids have been observed: itching, burning, irritation, dryness, folliculitis, hypertrichosis, acneform eruptions, hypopigmentations, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria.

OVERDOSE

Topically applied corticosteroids can be absorbed in sufficient amount to produce systemic effects.

MyOxin Dosage and Administration

SHAKE WELL BEFORE USING. The External auditory canal should be thoroughly cleansed and dried with a sterile cotton applicator. For adults, 4 to 5 drops of the suspension should be instilled into the affected ear 3 or 4 times daily. For infants and small children, 3 drops are suggested because of the smaller capacity of the ear canal. The patient should lie with the affected ear upward to instill the drops and this position maintained for 5 minutes to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear.

How is MyOxin Supplied

MyOxin Otic Suspension is supplied in 15mL amber glass bottles with dosage dropper and package insert NDC 58809-333-15

Rx Only

KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY.

Storage Conditions

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Manufactured for

GMPharmaceuticals, Inc.

Arlington, TX 76012

Rev. 6/2011

PRINCIPAL DISPLAY PANEL - 15 mL Bottle Carton

NDC 58809-333-15

MyOxin™

otic suspension

Chloroxylenol 1 mg

Benzocaine 15 mg

Hydrocortisone Acetate 10 mg

SHAKE WELL BEFORE USING

Rx Only

GMPharmaceuticals, Inc.

15 mL bottle

MyOxin  chloroxylenol, benzocaine, and hydrocortisone acetate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 58809-333 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chloroxylenol (Chloroxylenol) Chloroxylenol 1 mg  in 1 mL Benzocaine (Benzocaine) Benzocaine 15 mg  in 1 mL Hydrocortisone Acetate (Hydrocortisone) Hydrocortisone Acetate 10 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Water   PEG-12 Glyceryl Dimyristate   Polyoxyl 40 Castor Oil   Sodium Hydroxide   CARBOMER INTERPOLYMER TYPE A (55000 MPA.S)   Isopropyl Alcohol   Xanthan Gum   Potassium Sorbate

Product Characteristics Color WHITE (milky) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58809-333-15 1 BOTTLE In 1 BOX contains a BOTTLE, GLASS 1 15 mL In 1 BOTTLE, GLASS This package is contained within the BOX (58809-333-15)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
UNAPPROVED DRUG OTHER		08/01/2011

Labeler - GM Pharamceuticals, Inc (793000860)

Registrant - Sonar Products, Inc (104283945)

Establishment
Name	Address	ID/FEI	Operations
Sonar Products, Inc		104283945	MANUFACTURE

Revised: 07/2011GM Pharamceuticals, Inc

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• Otitis Externa

Benylin Childrens Night Coughs

1. Name Of The Medicinal Product

BENYLIN CHILDREN'S NIGHT COUGHS

2. Qualitative And Quantitative Composition

BENYLIN CHILDREN'S NIGHT COUGHS contains -

Active Ingredient	Mg/5 ml
Diphenhydramine Hydrochloride	7.0 mg
Levomenthol	0.55 mg

3. Pharmaceutical Form

A clear colourless syrup with no insoluble matter.

4. Clinical Particulars

4.1 Therapeutic Indications

BENYLIN CHILDREN'S NIGHT COUGHS is indicated for the relief of cough and its congestive symptoms, runny nose and sneezing, and in the treatment of hay fever and other allergic conditions affecting the upper respiratory tract. It is specially formulated for children and contains no artificial dyes or sucrose.

4.2 Posology And Method Of Administration

Route of Administration: Oral

Children under 6 years:

BENYLIN CHILDREN'S NIGHT COUGHS is contraindicated in children under the age of 6 years (see section 4.3).

Children 6 to 12 years:

Two 5 ml spoonfuls every 6 hours

No more than four doses should be given in any 24 hours.

Not to be used for more than five days without the advice of a doctor. Parents or carers should seek medical attention if the child's condition deteriorates during treatment.

Do not exceed the stated dose.

Keep out of the reach and sight of children.

4.3 Contraindications

BENYLIN CHILDREN'S NIGHT COUGHS is contraindicated in individuals with known hypersensitivity to the product or any of its constituents.

BENYLIN CHILDREN'S NIGHT COUGHS should not be administered to patients currently receiving monoamine oxidase inhibitors (MAOI) or those patients who have received treatment with MAOIs within the last two weeks (see section 4.5).

Not to be used in children under the age of 6 years.

4.4 Special Warnings And Precautions For Use

Diphenhydramine should not be taken by patients with susceptibility to angle-closure glaucoma or symptomatic prostatic hypertrophy unless directed by a doctor.

Alcohol or other potential sedating medicines should not be used concurrently with Benylin Children's Night Coughs

Patients with hepatic or moderate to severe renal dysfunction or urinary retention should exercise caution when using this product (see Pharmacokinetics - Renal/Hepatic Dysfunction).

The product may cause drowsiness. This product should not be used to sedate a child.

The label will state:

Do not use to sedate a child.

Do not exceed the stated dose.

Do not take with any other cough and cold medicine.

Ask a doctor before use if your child suffers from a chronic or persistent cough, if he/she has asthma, is suffering from an acute asthma attack or where cough is accompanied by excessive secretions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

CNS depressants: may enhance the sedative effects of CNS depressants including barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, antipsychotics and alcohol.

Antimuscarinic drugs: may have an additive muscarinic action with other drugs, such as atropine and some antidepressants.

MAOIs: Not to be used in patients taking MAOIs or within 14 days of stopping treatment as there is a risk of serotonin syndrome.

4.6 Pregnancy And Lactation

Diphenhydramine crosses the placenta and has been detected in breast milk. BENYLIN CHILDREN'S NIGHT COUGHS should only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing foetus or suckling infant.

4.7 Effects On Ability To Drive And Use Machines

This preparation may cause drowsiness, dizziness or blurred vision. If affected, the patient should not drive or operate machinery.

4.8 Undesirable Effects

Common side effects:

CNS effects: Drowsiness (usually diminishes within a few days), paradoxical stimulation, headache, psychomotor impairment.

Antimuscarinic effects: Urinary retention, dry mouth, blurred vision, gastrointestinal disturbances, thickened respiratory tract secretions.

Rare side effects:

Hypotension, extrapyramidal effects, dizziness, confusion, depression, sleep disturbances, tremor, convulsions, palpitation, arrhythmia, hypersensitivity reactions, blood disorders and liver dysfunction.

Adverse reactions to menthol at the low concentration present in BENYLIN CHILDREN'S NIGHT COUGHS are not anticipated.

4.9 Overdose

Signs and Symptoms:

Drowsiness, hyperpyrexia and anticholinergic effects. In children, CNS excitation, including hallucinations and convulsions may appear; with larger doses, coma or cardiovascular collapse may follow.

Treatment

Treatment of overdose with BENYLIN CHILDREN'S NIGHT COUGHS is likely to involve supportive care and rapid gastric emptying with Syrup of Ipecac induced emesis or gastric lavage. In cases of acute poisoning, activated charcoal may be useful. Seizures may be controlled with Diazepam or Thiopental Sodium. In addition to supportive care, the intravenous use of Physostigmine may be efficacious in antagonising severe anticholinergic symptoms.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diphenhydramine is a potent antihistamine and antitussive with anticholinergic properties. Recent experiments have shown that the antitussive action is discrete from H₁-receptor blockade and is located in the brain stem.

Menthol has mild local anaesthetic and decongestant properties.

5.2 Pharmacokinetic Properties

Diphenhydramine is well absorbed from the gastrointestinal tract. Peak serum levels are reached at between 2-2.5 hours after an oral dose. Duration of activity is between 4 - 8 hours. The drug is widely distributed throughout the body, including the CNS, and some 78% is bound to plasma proteins. Estimates of the volume of distribution lie in the range 3.3 - 6.8 l/kg.

Diphenhydramine experiences extensive first-pass metabolism, undergoing two successive N-Demethylations; the resultant amine is then oxidised to a carboxylic acid. Values for plasma clearance lie in the range 600 - 1300 ml/min and the terminal elimination half life lies in the range 3.4 - 9.3 hours. Little unchanged drug is excreted in the urine.

Pharmacokinetic studies in elderly subjects indicate no major differences in drug distribution or elimination compared with younger adults.

Menthol: After absorption, menthol is conjugated in the liver and excreted both in urine and bile as the glucuronide.

Renal Dysfunction

The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR).

Hepatic Dysfunction

After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease. However, the mean plasma clearance and apparent volume of distribution were not significantly affected.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium benzoate

Citric acid monohydrate

Sodium citrate

Saccharin sodium

Sodium carboxymethylcellulose 7MXF

Glycerol

Sorbitol 70% (non crystalline)

Concentrated raspberry essence

Ethanol 96%

Purified water

6.2 Incompatibilities

None stated

6.3 Shelf Life

36 months unopened

6.4 Special Precautions For Storage

Store below 30ºC

6.5 Nature And Contents Of Container

125.000 ml, 30.000 ml Round amber glass bottles with roll-on-pilfer-proof (ROPP) aluminium caps containing melinex-faced pulpboard wad

or

3 piece plastic child resistant, tamper evident closure fitted with a polyester faced wad or polyethylene/expanded polyethylene laminated wad

or

2 piece plastic child resistant, tamper evident closure fitted with a PET wad.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

Administrative Data

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0044

9. Date Of First Authorisation/Renewal Of The Authorisation

Date granted: 16 June 1997

10. Date Of Revision Of The Text

5^th March 2010

Amias Tablets

1. Name Of The Medicinal Product

Amias 2 mg Tablets.

Amias 4 mg Tablets.

Amias 8 mg Tablets.

Amias 16 mg Tablets.

Amias 32 mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 2 mg candesartan cilexetil.

Each tablet contains 95.4 mg lactose monohydrate

Each tablet contains 4 mg candesartan cilexetil.

Each tablet contains 93.4 mg lactose monohydrate.

Each tablet contains 8 mg candesartan cilexetil.

Each tablet contains 89.4 mg lactose monohydrate.

Each tablet contains 16 mg candesartan cilexetil.

Each tablet contains 81.3 mg lactose monohydrate.

Each tablet contains 32 mg candesartan cilexetil.

Each tablet contains 162.7 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

Amias 2 mg Tablets are round white tablets.

Amias 4 mg Tablets are round white tablets with a single score line on both sides.

Amias 8 mg Tablets are round pale pink tablets with a single score line on both sides.

Amias 16 mg Tablets are round light pink tablets with one convex side and one scored flat side, embossing 16 on convex side.

Amias 32 mg Tablets are round light pink tablets with convex faces, debossed 32 on one face and scored on the other face.

4. Clinical Particulars

4.1 Therapeutic Indications

Amias is indicated for the:

• Treatment of essential hypertension in adults.

• Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction

4.2 Posology And Method Of Administration

Posology in Hypertension

The recommended initial dose and usual maintenance dose of Amias is 8 mg once daily. Most of the antihypertensive effect is attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response.

Amias may also be administered with other antihypertensive agents. Addition of hydrochlorothiazide has been shown to have an additive antihypertensive effect with various doses of Amias.

Elderly population

No initial dose adjustment is necessary in elderly patients.

Patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion (see section 4.4).

Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis. The dose should be titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine < 15 ml/min) (see section 4.4).

Patients with hepatic impairment

An initial dose of 4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. Amias is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3 and 5.2).

Black patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients. Consequently, uptitration of Amias and concomitant therapy may be more frequently needed for blood pressure control in black patients than in non-black patients (see section 5.1).

Posology in Heart Failure

The usual recommended initial dose of Amias is 4 mg once daily. Up-titration to the target dose of 32 mg once daily (maximum dose) or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see section 4.4). Evaluation of patients with heart failure should always comprise assessment of renal function including monitoring of serum creatinine and potassium. Amias can be administered with other heart failure treatment, including ACE inhibitors, beta

Special patient populations

No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion or renal impairment or mild to moderate hepatic impairment.

Paediatric Population

The safety and efficacy of Amias in children aged between birth and 18 years have not been established in the treatment of hypertension and heart failure. No data are available.

Method of administration

Oral use.

Amias should be taken once daily with or without food.

The bioavailability of candesartan is not affected by food.

4.3 Contraindications

Hypersensitivity to candesartan cilexetil or to any of the excipients.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Severe hepatic impairment and/or cholestasis.

4.4 Special Warnings And Precautions For Use

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Amias.

When Amias is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine < 15 ml/min). In these patients Amias should be carefully titrated with thorough monitoring of blood pressure.

Evaluation of patients with heart failure should include periodic assessments of renal function, especially in elderly patients 75 years or older, and patients with impaired renal function. During dose titration of Amias, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine> 265 μmol/l (> 3 mg/dl).

Concomitant therapy with an ACE inhibitor in heart failure

The risk of adverse reactions, especially renal function impairment and hyperkalaemia, may increase when Amias is used in combination with an ACE inhibitor (see section 4.8). Patients with such treatment should be monitored regularly and carefully.

Haemodialysis

During dialysis the blood pressure may be particularly sensitive to AT₁-receptor blockade as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

There is no experience regarding the administration of Amias in patients with a recent kidney transplantation.

Hypotension

Hypotension may occur during treatment with Amias in heart failure patients. It may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Amias is not recommended in this population.

Hyperkalaemia

Concomitant use of Amias with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients. Monitoring of potassium should be undertaken as appropriate.

In heart failure patients treated with Amias, hyperkalaemia may occur. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium

General

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with AIIRAs. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.

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

Pregnancy

AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate (see section 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with AIIRAs. Use of candesartan with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

4.6 Pregnancy And Lactation

Pregnancy

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of Amias during breastfeeding, Amias is not recommended and alternative treatments with better established safety profiles during breast

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of candesartan on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or weariness may occur during treatment with Amias.

4.8 Undesirable Effects

Treatment of Hypertension

In controlled clinical studies adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose or age. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%) and placebo (3.2%).

In a pooled analysis of clinical trial data of hypertensive patients, adverse reactions with candesartan cilexetil were defined based on an incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence seen with placebo. By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.

The table below presents adverse reactions from clinical trials and post-marketing experience.

The frequencies used in the tables throughout section 4.8 are: very common (

System Organ Class	Frequency	Undesirable Effect
Infections and infestations	Common	Respiratory infection
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia and agranulocytosis
Metabolism and nutrition disorders	Very rare	Hyperkalaemia, hyponatraemia
Nervous system disorders	Common	Dizziness/vertigo, headache
Gastrointestinal disorders	Very rare	Nausea
Hepato-biliary disorders	Very rare	Increased liver enzymes, abnormal hepatic function or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angioedema, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders	Very rare	Back pain, arthralgia, myalgia
Renal and urinary disorders	Very rare	Renal impairment, including renal failure in susceptible patients (see section 4.4)

Laboratory findings

In general, there were no clinically important influences of Amias on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. No routine monitoring of laboratory variables is usually necessary for patients receiving Amias. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Treatment of Heart Failure

The adverse experience profile of Amias in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing Amias in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events. The most commonly reported adverse reactions were hyperkalaemia, hypotension and renal impairment. These events were more common in patients over 70 years of age, diabetics, or subjects who received other medicinal products which affect the renin-angiotensin-aldosterone system, in particular an ACE inhibitor and/or spironolactone.

The table below presents adverse reactions from clinical trials and post-marketing experience.

System Organ Class	Frequency	Undesirable Effect
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia and agranulocytosis
Metabolism and nutrition disorders	Common	Hyperkalaemia
	Very rare	Hyponatraemia
Nervous system disorders	Very rare	Dizziness, headache
Vascular disorders	Common	Hypotension
Gastrointestinal disorders	Very rare	Nausea
Hepato-biliary disorders	Very rare	Increased liver enzymes, abnormal hepatic function or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angioedema, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders	Very rare	Back pain, arthralgia, myalgia
Renal and urinary disorders	Common	Renal impairment, including renal failure in susceptible patients (see section 4.4)

Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with Amias for the indication of heart failure. Periodic monitoring of serum creatinine and potassium is recommended (see section 4.4).

4.9 Overdose

Symptoms

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672mg candesartan cilexetil) patient recovery was uneventful.

Management

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic saline solution. Sympathomimetic medicinal products may be administered if the above-mentioned measures are not sufficient.

Candesartan is not removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group:

Angiotensin II antagonists, plain, ATC code: C09CA06

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT₁) receptor.

Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT₁ receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the angiotensin II (AT₁) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.

Hypertension

In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, without reflex increase in heart rate. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.

After administration of a single dose of candesartan cilexetil, onset of antihypertensive effect generally occurs within 2 hours. With continuous treatment, most of the reduction in blood pressure with any dose is generally attained within four weeks and is sustained during long-term treatment. According to a meta-analysis, the average additional effect of a dose increase from 16 mg to 32 mg once daily was small. Taking into account the inter-individual variability, a more than average effect can be expected in some patients. Candesartan cilexetil once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised, double-blind studies in a total of 1,268 patients with mild to moderate hypertension. The trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001).

When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. An increased antihypertensive effect is also seen when candesartan cilexetil is combined with amlodipine or felodipine.

Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive effect in black patients (usually a low-renin population) than in non-black patients. This is also the case for candesartan. In an open label clinical experience trial in 5,156 patients with diastolic hypertension, the blood pressure reduction during candesartan treatment was significantly less in black than non-black patients (14.4/10.3 mmHg vs 19.0/12.7 mmHg, p<0.0001/p<0.0001).

Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. In a 3-month clinical study in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95%CI 15

The effects of candesartan cilexetil 8

Heart Failure

Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity (CHARM) programme.

This placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF

In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, hazard ratio (HR) 0.77 (95%CI: 0.67 to 0.89, p< 0.001). This corresponds to a relative risk reduction of 23%. Of candesartan patients 33.0% (95%CI: 30.1 to 36.0) and of placebo patients 40.0% (95%CI: 37.0 to 43.1) experienced this endpoint, absolute difference 7.0% (95%CI: 11.2 to 2.8). Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.80 (95%CI: 0.70 to 0.92, p=0.001). Of candesartan patients 36.6% (95%CI: 33.7 to 39.7) and of placebo patients 42.7% (95%CI: 39.6 to 45.8) experienced this endpoint, absolute difference 6.0% (95%CI: 10.3 to 1.8). Both the mortality and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).

In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, HR 0.85 (95%CI: 0.75 to 0.96, p=0.011). This corresponds to a relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2 to 40.6) and of placebo patients 42.3% (95%CI: 39.6 to 45.1) experienced this endpoint, absolute difference 4.4% (95%CI: 8.2 to 0.6). Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.87 (95%CI: 0.78 to 0.98, p=0.021). Of candesartan patients 42.2% (95%CI: 39.5 to 45.0) and of placebo patients 46.1% (95%CI: 43.4 to 48.9) experienced this endpoint, absolute difference 3.9% (95%CI: 7.8 to 0.1). Both the mortality and morbidity components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).

In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first CHF hospitalisation, HR 0.89 (95%CI: 0.77 to 1.03, p=0.118).

All-cause mortality was not statistically significant when examined separately in each of the three CHARM studies. However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added, HR 0.88 (95%CI: 0.79 to 0.98, p=0.018) and all three studies, HR 0.91 (95%CI: 0.83 to 1.00, p=0.055).

The beneficial effects of candesartan were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.

In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF

5.2 Pharmacokinetic Properties

Absorption and distribution

Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (C_max) is reached 3versus time curve (AUC) of candesartan is not significantly affected by food.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is 0.1 l/kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.

Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of ¹⁴C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.

Pharmacokinetics in special populations

In the elderly (over 65 years) C_max and AUC of candesartan are increased by approximately 50% and 80%, respectively in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of Amias in young and elderly patients (see section 4.2).

In patients with mild to moderate renal impairment C_max and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t_½ was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t_½ of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in patients undergoing haemodialysis was similar to that in patients with severe renal impairment.

In two studies, both including patients with mild to moderate hepatic impairment, there was an increase in the mean AUC of candesartan of approximately 20% in one study and 80% in the other study (see section 4.2). There is no experience in patients with severe hepatic impairment.

5.3 Preclinical Safety Data

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.

Foetotoxicity has been observed in late pregnancy (see section 4.6).

Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.

There was no evidence of carcinogenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Carmellose calcium

Hydroxypropyl cellulose

Iron oxide red (E172) (8, 16 and 32 mg tablets only)

Lactose monohydrate

Magnesium stearate

Maize starch

Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

Polypropylene blister.

2 mg tablets: Blister packs of 7 and 14 tablets.

4 mg, 8 mg, 16 mg and 32 mg tablets: Blister packs of 7, 14, 20, 28, 50, 56, 98, 98x1 (single dose unit), 100 or 300 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Takeda UK Limited

Takeda House

Mercury Park, Wycombe Lane

Wooburn Green, High Wycombe

Buckinghamshire HP10 0HH

8. Marketing Authorisation Number(S)

PL 16189/0001

PL 16189/0002

PL 16189/0003

PL 16189/0004

PL 16189/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 15 December 1998

Date of latest renewal: 29 April 2002

10. Date Of Revision Of The Text

July 2010