Savella

Pronunciation: mil-NA-si-pran
Generic Name: Milnacipran
Brand Name: Savella

Savella is similar to certain antidepressant medicines. Antidepressants may increase the risk of suicidal thoughts or actions in children, teenagers, and young adults. However, depression and certain other mental problems may also increase the risk of suicide. Talk with the patient's doctor to be sure that the benefits of using Savella outweigh the risks.

Families and caregivers must closely watch patients who take Savella. It is important to keep in close contact with the patient's doctor. Tell the doctor right away if the patient has symptoms like worsened depression, suicidal thoughts, or changes in behavior. Discuss any questions with the patient's doctor.

Savella is not approved for use in children or to treat depression.

Savella is used for:

Treating fibromyalgia.

Savella is a serotonin-norepinephrine reuptake inhibitor (SNRI). Exactly how Savella works to treat fibromyalgia is not known. It may work by restoring the balance of certain natural substances in the brain (serotonin and norepinephrine).

Do NOT use Savella if:

• you are allergic to any ingredient in Savella


• you have uncontrolled narrow-angle glaucoma or end-stage kidney disease


• you are taking or have taken a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days


• you are taking tryptophan, a selective serotonin reuptake inhibitor (SSRI) (eg, fluoxetine), or another SNRI (eg, duloxetine)

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

Before using Savella:

Some medical conditions may interact with Savella. 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 (eg, aspirin, tartrazine)


• if you or a family member has a history of bipolar disorder (manic-depression), other mental or mood problems, suicidal thoughts or attempts, or alcohol or substance abuse


• if you have a history of seizures, heart problems (eg, heart failure, irregular heartbeat), recent heart attack, high blood pressure, bleeding problems, kidney problems, liver problems, urinary blockage or trouble urinating, enlarged prostate, or increased eye pressure (eg, glaucoma)


• if you are dehydrated, have low blood sodium levels, or drink alcohol


• if you are being switched to Savella after taking another medicine called clomipramine

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

• 5-HT₁ receptor agonists (eg, sumatriptan), lithium, MAOIs (eg, phenelzine), rasagiline, SNRIs (eg, venlafaxine), SSRIs (eg, fluoxetine, fluvoxamine), St. John's wort, tramadol, or tryptophan because severe side effects, such as a reaction that may include fever, rigid muscles, blood pressure changes, mental changes, confusion, irritability, agitation, delirium, and coma, may occur


• Diuretics (eg, furosemide, hydrochlorothiazide) because the risk of low blood sodium levels may be increased


• Anticoagulants (eg, warfarin), aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDS) (eg, ibuprofen) because the risk of bleeding may be increased by Savella


• Digoxin, epinephrine, or norepinephrine because the risk of irregular heartbeat or blood pressure changes may be increased.


• Clonidine because its effectiveness may be decreased by Savella

This may not be a complete list of all interactions that may occur. Ask your health care provider if Savella 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 Savella:

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

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


• Take Savella by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Take Savella on a regular schedule to get the most benefit from it. Taking Savella at the same time each day will help you remember to take it.


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


• Do not suddenly stop taking Savella without checking with your doctor. Side effects may occur. They may include mental or mood changes, numbness or tingling of the skin, dizziness, confusion, headache, nausea, nightmare, ringing in the ears, seizures, trouble sleeping, unusual tiredness, or vomiting. You will be closely monitored when you start Savella and whenever a change in dose is made.


• If you miss a dose of Savella, 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 Savella.

Important safety information:

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


• Do not drink alcohol while you are taking Savella.


• Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Savella; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Several weeks may pass before your symptoms improve. Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Children, teenagers, and young adults who take Savella may be at increased risk for suicidal thoughts or actions. Adults may also be affected. The risk may be greater in patients who have had suicidal thoughts or actions in the past. The risk may also be greater in patients who have had bipolar (manic-depressive) illness, or if their family members have had it. Watch patients who take Savella closely. Contact the doctor at once if new, worsened, or sudden symptoms such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur.


• Serotonin syndrome is a possibly fatal syndrome that can be caused by Savella. Your risk may be greater if you take Savella with certain other medicines (eg, SSRIs, "triptans"). Symptoms may include agitation; coma; confusion; excessive sweating; fast or irregular heartbeat; fever; hallucinations; nausea, vomiting, or diarrhea; tremor. Contact your doctor at once if you have any of these symptoms.


• Neuroleptic malignant syndrome (NMS) is a possibly fatal syndrome that can be caused by Savella. Symptoms may include fever; stiff muscles; confusion; abnormal thinking; fast or irregular heartbeat; and sweating. Contact your doctor at once if you have any of these symptoms.


• If your doctor tells you to stop taking Savella, you will need to wait for at least 5 days before beginning to take certain other medicines (eg, MAOIs). Ask your doctor when you should start to take your new medicines after you have stopped taking Savella.


• If you are being switched to Savella after taking another medicine called clomipramine, you may have an increased risk for certain side effects (eg, dizziness or lightheadedness when standing, exaggerated sense of well-being). Contact your doctor if any of these symptoms occur.


• Lab tests, including blood pressure, heart rate, and liver function, may be performed while you use Savella. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Savella with caution in the ELDERLY; they may be more sensitive to its effects, especially low blood sodium levels.


• Caution is advised if using Savella in CHILDREN; they may be more sensitive to its effects, especially increased risk of suicidal thoughts or actions.


• Savella should not be used in CHILDREN younger than 17 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Savella may cause harm to the fetus if it is used during the last 3 months of pregnancy. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Savella while you are pregnant. It is not known if Savella is found in breast milk. Do not breast-feed while taking Savella.

Do not suddenly stop taking Savella. Some conditions may become worse when the medicine is suddenly stopped. Your dose may need to be slowly lowered to avoid side effects.

Possible side effects of Savella:

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:

Constipation; decreased sexual desire or ability; dizziness; dry mouth; headache; hot flush; increased sweating; loss of appetite; nausea; trouble sleeping; 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); bizarre behavior; bloody or black, tarry stools; confusion; dark urine; decreased concentration; decreased coordination; excessive sweating; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; hallucinations; memory problems; muscle pain or weakness; new or worsening agitation, anxiety, depression, panic attacks, aggressiveness, impulsiveness, irritability, hostility, restlessness, or inability to sit still; pale stools; red, swollen, blistered, or peeling skin; seizures; severe or persistent headache or dizziness; severe or persistent nausea, vomiting, or diarrhea; severe or persistent trouble sleeping; stomach pain; suicidal thoughts or attempts; tremor; trouble urinating; unusual bruising or bleeding; unusual or severe mental or mood changes; unusual weakness; yellowing of the skin or eyes.

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: Savella 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; coma; confusion; dark urine; severe or persistent dizziness, drowsiness, or headache; trouble breathing; yellowing of the skin or eyes.

Proper storage of Savella:

Store Savella at 77 degrees F (25 degrees C). Brief storage 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 Savella out of the reach of children and away from pets.

General information:

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


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


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


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

This information is a summary only. It does not contain all information about Savella. 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 Savella resources

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

• Savella Prescribing Information (FDA)


• Savella Advanced Consumer (Micromedex) - Includes Dosage Information


• Savella Consumer Overview

Compare Savella with other medications

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Eligard

leuprolide acetate

Dosage Form: injectable suspension
Eligard® 7.5 mg, 22.5 mg, 30 mg, 45 mg

(leuprolide acetate for injectable suspension)

Eligard Description

Eligard® is a sterile polymeric matrix formulation of leuprolide acetate for subcutaneous injection. It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four- or six-month therapeutic period.

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. The analog possesses greater potency than the natural hormone. The chemical name is 5 - oxo - L - prolyl - L - histidyl - L - tryptophyl - L - seryl - L - tyrosyl - D - leucyl - L - leucyl - L - arginyl - N - ethyl - L - prolinamide acetate (salt) with the following structural formula:

Eligard® is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. Eligard® is administered subcutaneously, where it forms a solid drug delivery depot.

One syringe contains the ATRIGEL® Delivery System and the other contains leuprolide acetate. ATRIGEL® is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).

Refer to Table 1 for the delivery system composition and constituted product formulation for each Eligard® product.

Table 1. Eligard® Delivery System Composition and Constituted Product Formulation

		Eligard® 7.5 mg	Eligard® 22.5 mg	Eligard® 30 mg	Eligard® 45 mg
ATRIGEL® Delivery System Syringe	Polymer	PLGH	PLG	PLG	PLG
	Polymer description	Copolymer containing carboxyl endgroups	Copolymer with hexanediol	Copolymer with hexanediol	Copolymer with hexanediol
	Polymer DL-lactide to Glycolide Molar Ratio	50:50	75:25	75:25	85:15
Constituted Product	Polymer delivered	82.5 mg	158.6 mg	211.5 mg	165 mg
	NMP delivered	160.0 mg	193.9 mg	258.5 mg	165 mg
	Leuprolide acetate delivered	7.5 mg	22.5 mg	30 mg	45 mg
	Approximate Leuprolide free base equivalent	7.0 mg	21 mg	28 mg	42 mg
	Approximate administered formulation weight	250 mg	375 mg	500 mg	375 mg
	Approximate injection volume	0.25 mL	0.375 mL	0.5 mL	0.375 mL

Eligard - Clinical Pharmacology

Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.

PHARMACODYNAMICS

Following the first dose of Eligard®, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all Eligard® concentrations.

Continued monthly treatment with Eligard® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (Figure 1).

One patient received less than a full dose of Eligard® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (Figure 2).

One patient withdrew from the Eligard® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 3).

One patient at Day 1 and another patient at Day 29 were withdrawn from the Eligard® 45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 4).

Leuprolide acetate is not active when given orally.

PHARMACOKINETICS

Absorption

Eligard® 7.5 mg

The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 1. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).

 

Figure 1 Pharmacokinetic/Pharmacodynamic Response (N=20) to Eligard® 7.5 mg – Patients Dosed Initially and at Months 1 and 2

A reduced number of sampling timepoints resulted in the apparent decrease in Cmax values with the second and third doses of Eligard® 7.5 mg (Figure 1).

Eligard® 22.5 mg

The pharmacokinetics/pharmacodynamics observed during two injections every three months (Eligard® 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 2. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 5 hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).

 

Figure 2 Pharmacokinetic/Pharmacodynamic Response (N=22) to Eligard® 22.5 mg – Patients Dosed Initially and at Month 3

Eligard® 30 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (Eligard® 30 mg ) in 24 patients with advanced prostate cancer is shown in Figure 3. Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (Cmax) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL).

 

Figure 3 Pharmacokinetic/Pharmacodynamic Response (N=24) to Eligard® 30 mg – Patients Dosed Initially and at Month 4

Eligard® 45 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (Eligard® 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 4. Mean serum leuprolide concentrations rose to 82.0 ng/mL and 102 ng/mL (Cmax) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).

 

Figure 4 Pharmacokinetic/Pharmacodynamic Response (N=27) to Eligard® 45 mg - Patients Dosed Initially and at Month 6

There was no evidence of significant accumulation during repeated dosing. Nondetectable leuprolide plasma concentrations have been occasionally observed during Eligard® administration, but testosterone levels were maintained at castrate levels.

Distribution

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L.1 In vitro binding to human plasma proteins ranged from 43% to 49%.

1

Sennello LT et al. Single-dose pharmacokinetics of leuprolide in humans following intravenous and subcutaneous administration. J Pharm Sci 1986; 75(2): 158–160.

Metabolism

In healthy male volunteers, a 1-mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.1

No drug metabolism study was conducted with Eligard®. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.

Excretion

No drug excretion study was conducted with Eligard®.

Special Populations

Geriatrics

The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.

Pediatrics

The safety and effectiveness of Eligard® in pediatric patients have not been established (see CONTRAINDICATIONS).

Race

In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table 2 for distribution of study patients by race.

Table 2. Race Characterization of Study Patients

Race	Eligard® 7.5 mg	Eligard® 22.5 mg	Eligard® 30 mg	Eligard® 45 mg
White	26	19	18	17
Black	-	4	4	7
Hispanic	2	2	2	3

Renal and Hepatic Insufficiency

The pharmacokinetics of Eligard® in hepatically and renally impaired patients have not been determined

Drug-Drug Interactions

No pharmacokinetic drug-drug interaction studies were conducted with Eligard®.

Clinical Studies

One open-label, multicenter study was conducted with each Eligard® formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (Table 3). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (Figures 5–8).

During the AGL9904 study using Eligard® 7.5 mg, once testosterone suppression was achieved, no patients (0%) demonstrated breakthrough (concentration >50 ng/dL) at any time in the study.

During the AGL9909 study using Eligard® 22.5 mg, once testosterone suppression was achieved, only one patient (< 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection.

During the AGL0001 study using Eligard® 30 mg, once testosterone suppression was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection. In this patient, castrate suppression was reported for all other timepoints. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection. In this patient, castrate suppression was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection. In this patient, castrate suppression was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported.

During the AGL0205 study using Eligard® 45 mg, once testosterone suppression was achieved, one patient (<1%) demonstrated breakthrough. This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL. At Month 12 (Day 336), his testosterone was 210 ng/dL.

Table 3. Summary of Eligard® Clinical Studies

			7.5 mg	22.5 mg	30 mg	45 mg
* One patient received less than a full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment. † All non-evaluable patients who attained castration by Day 28 maintained castration at each timepoint up to and including the time of withdrawal. ‡ One patient withdrew on Day 14. All 7 non-evaluable patients who had achieved castration by Day 28 maintained castration at each timepoint, up to and including the time of withdrawal. § Two patients were withdrawn prior to the Month 1 blood draw. One patient did not achieve castration and was withdrawn on Day 85. All 5 non-evaluable patients who attained castration by Day 28, maintained castration at each timepoint up to and including the time of withdrawal. ¶ Two patients withdrew for reasons unrelated to drug.
Study number			AGL9904	AGL9909	AGL0001	AGL0205
Total Number of patients			120 (117 completed)	117* (111 completed†)	90 (82 completed‡)	111 (103 completed§)
Jewett Stages	Stage A		-	2	2	5
	Stage B		-	19	38	43
	Stage C		89	60	16	19
	Stage D		31	36	34	44
Treatment			6 monthly injections	1 injection (4 patients)	1 injection (5 patients)	1 injection (5 patients)
				2 injections, one every three months (113 patients)	2 injections, one every four months (85 patients)	2 injections, one every six months (106 patients)
Duration of therapy			6 months	6 months	8 months	12 months
Mean testosterone concentration (ng/dL)		Baseline	361.3	367.1	385.5	367.7
		Day 2	574.6 (Day 3)	588.0	610.0	588.6
		Day 14	Below Baseline (Day 10)	Below Baseline	Below Baseline	Below Baseline
		Day 28	21.8	27.7 (Day 21)	17.2	16.7
		Conclusion	6.1	10.1	12.4	12.6
Number of patients below castrate threshold (≤ 50 ng/dL)		Day 28	112 of 119 (94.1%)	115 of 116 (99%)	85 of 89 (96%)	108 of 109 (99.1%)
		Day 35	-	116 (100%)	-	-
		Day 42	119 (100%)	-	89 (100%)	-
		Conclusion	117¶ (100%)	111 (100%)	81 (99%)	102 (99%)

Figure 5 Eligard® 7.5 mg Mean Serum Testosterone Concentrations (n=117)

 

Figure 6 Eligard® 22.5 mg Mean Serum Testosterone Concentrations (n=111)

 

Figure 7 Eligard® 30 mg Mean Serum Testosterone Concentrations (n=90)

 

Figure 8 Eligard® 45 mg Mean Serum Testosterone Concentrations (n=103)

Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to Table 4 for a summary of the effectiveness of Eligard® in reducing serum PSA values.

Table 4 Effect of Eligard® on Patient Serum PSA Values

Eligard®	7.5 mg	22.5 mg	30 mg	45 mg
* Among patients who presented with elevated levels at Baseline
Mean PSA Reduction at Study Conclusion	94%	98%	86%	97%
Patients with Normal PSA at Study Conclusion*	94%	91%	93%	95%

Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. Refer to Table 5 for a summary of these endpoints.

Table 5 Secondary Efficacy Endpoints

		Eligard® 7.5 mg	Eligard® 22.5 mg	Eligard® 30 mg	Eligard® 45 mg
* WHO Status = 0 classified as "fully active." † WHO Status = 1 classified as "restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature." ‡ WHO Status = 2 classified as "ambulatory but unable to carry out work activities." § Pain score scale: 1 (no pain) to 10 (worst pain possible).
Baseline	WHO Status = 0*	88%	94%	90%	90%
	WHO Status = 1†	11%	6%	10%	7%
	WHO Status = 2‡				3%
	Mean Bone Pain§ (range)	1.22 (1–9)	1.20 (1–9)	1.20 (1–7)	1.38 (1–7)
	Mean Urinary Pain (range)	1.12 (1–5)	1.02 (1–2)	1.01 (1–2)	1.22 (1–8)
	Mean Urinary Signs and Symptoms (range)	Low	1.09 (1–4)	Low	Low
	Number of Patients with Prostate Abnormalities	102 (85%)	96 (82%)	66 (73%)	89 (80%)
		Month 6	Month 6	Month 8	Month 12
Follow-up	WHO Status = 0	Unchanged	96%	87%	94%
	WHO Status = 1	Unchanged	4%	12%	5%
	WHO Status = 2			1%	1%
	Mean Bone Pain (range)	1.26 (1–7)	1.22 (1–5)	1.19 (1–8)	1.31 (1–8)
	Mean Urinary Pain (range)	1.07 (1–8)	1.10 (1–8)	1.00 (1–1)	1.07 (1–5)
	Mean Urinary Signs and Symptoms (range)	Modestly Decreased	1.18 (1–7)	Modestly Decreased	Modestly Decreased
	Number of Patients with Prostate Abnormalities	77 (64%)	76 (65%)	54 (60%)	60 (58%)

Indications and Usage for Eligard

Eligard® is indicated for the palliative treatment of advanced prostate cancer.

Contraindications

1. Eligard® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of Eligard®. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.2


2. Eligard® is contraindicated in women and in pediatric patients and was not studied in women or children. Moreover, leuprolide acetate can cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.

2

MacLeod TL et al. Anaphylactic reaction to synthetic luteinizing hormone releasing hormone. Fertil Steril 1987 Sept; 48(3): 500–502.

Warnings

Eligard® 7.5 mg 22.5 mg 30 mg, like other LH-RH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. Eligard® 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction. Isolated cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using LH-RH agonists (see PRECAUTIONS).

If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.

Precautions

General

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS section).

Laboratory Tests

Response to Eligard® should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically.

In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks.

Castrate testosterone levels were maintained for the duration of the treatment with Eligard® 7.5 mg. No increases to above the castrate level occurred in any of the patients.

Castrate levels were generally maintained for the duration of treatment with Eligard® 22.5 mg.

Once castrate levels were achieved with Eligard® 30 mg, most (86/89) patients remained suppressed throughout the study.

Once castrate levels were achieved with Eligard® 45 mg, only one patient (< 1%) experienced a breakthrough, with testosterone levels > 50 ng/dL.

Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Drug Interactions

See PHARMACOKINETICS.

Drug/Laboratory Test Interactions

Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with Eligard®.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with Eligard® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential.

Pregnancy

Teratogenic Effects

Pregnancy category X

(see CONTRAINDICATIONS).

Pediatric Use

Eligard® is contraindicated in pediatric patients and was not studied in children (see CONTRAINDICATIONS).

Adverse Reactions

The safety of all Eligard® formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of Eligard® 7.5 mg was evaluated in 8 surgically castrated males (Table 7). Eligard®, like other LH-RH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms (see WARNINGS and PRECAUTIONS).

During the clinical trials, injection sites were closely monitored. Refer to Table 6 for a summary of reported injection site events.

Table 6 Reported Injection Site Adverse Events

	7.5 mg	22.5 mg	30 mg	45 mg
* Following injection of Eligard® 30 mg, three of the 35 burning/stinging events were reported as moderate. † A single event reported as moderate pain resolved within two minutes and all 3 mild pain events resolved within several days following injection of Eligard® 30 mg. ‡ Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of Eligard® 45 mg. § Erythema was reported following 2 injections of Eligard® 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injections. ¶ Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (<1%) study injections of Eligard® 45 mg.
Study Number	AGL9904	AGL9909	AGL0001	AGL0205
Number of patients	120	117	90	111
Treatment	1 injection every month up to 6 months	1 injection every 3 months up to 6 months	1 injection every 4 months up to 8 months	1 injection every 6 months up to 12 months
Number of injections	716	230	175	217
Transient burning/stinging	248 (34.6%) injections;84% reported as mild	50 (21.7%) injections; 86% reported as mild	35 (20%) injections; 100% reported as mild	35 (16%) injections; 91.4% reported as mild*
Pain (generally brief and mild)	4.3% of injections (18.3% of patients)	3.5% of injections (6.0% of patients)	2.3% of injections† (3.3% of patients)	4.6% of injections‡
Erythema (generally brief and mild)	2.6% of injections (12.5% of patients)	0.9% of injections§ (1.7% of patients)	1.1% of injections (2.2% of patients)
Bruising (Mild)	2.5% of injections (11.7% of patients)	1.7% of injections (3.4% of patients)		2.3% of injections¶
Pruritis	1.4% of injections (9.2% of patients)	0.4% of injections (0.9% of patients)
Induration	0.4% of injections (2.5% of patients)
Ulceration	0.1% of injections (> 0.8% of patients)

These localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.

The following possibly or probably related systemic adverse events occurred during clinical trials with Eligard®, and were reported in > 2% of patients (Table 7). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.

Table 7 Summary of Possible or Probably Related Systemic Adverse Events Reported by > 2% of Patients treated with Eligard®

		7.5 mg	7.5 mg	22.5 mg	30 mg	45 mg
In the patient populations studied with Eligard® 7.5 mg, a total of 86 hot flashes/sweats adverse events were reported in 70 patients. Of these, 71 events (83%) were mild; 14 (16%) were moderate; 1 (1%) was severe. In the patient population studied with Eligard® 22.5 mg, a total of 84 hot flashes/sweats adverse events were reported in 66 patients. Of these, 73 events (87%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with Eligard® 30 mg, a total of 75 hot flash adverse events were reported in 66 patients. Of these, 57 events (76%) were mild; 16 (21%) were moderate; 2 (3%) were severe. In the patient population studied with Eligard® 45 mg, a total of 89 hot flash adverse events were reported in 64 patients. Of these, 62 events (70%) were mild; 27 (30%) were moderate; none were severe.
* Expected pharmacological consequences of testosterone suppression.
Study Number		AGL9904	AGL9802	AGL9909	AGL0001	AGL0205
Number of patients		120	8	117	90	111
Treatment		1 injection every month up to 6 months	1 injection (surgically castrated patients)	1 injection every 3 months up to 6 months	1 injection every 4 months up to 8 months	1 injection every 6 months up to 12 months
Body System	Adverse Event	Number (Percent)
Body as a Whole	Malaise and Fatigue	21 (17.5 %)		7 (6.0%)	12 (13.3%)	13 (11.7%)
	Weakness					4 (3.6%)
Nervous System	Dizziness	4 (3.3%)			4 (4.4%)
Vascular

Nimotop 30mg Tablets

1. Name Of The Medicinal Product

Nimotop 30mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 30mg nimodipine.

3. Pharmaceutical Form

Film-coated tablet.

Yellow, round biconvex tablets with “SK” marked on one side and the Bayer cross marked on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Nimodipine is indicated for the prevention of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage.

4.2 Posology And Method Of Administration

Aneurysmal subarachnoid haemorrhage:

Prophylactic administration - Adults

The recommended dose is two tablets at 4-hourly intervals (total daily dose 360 mg) to be taken with water. Prophylactic administration should commence within four days of onset of subarachnoid haemorrhage and should be continued for 21 days.

In the event of surgical intervention, administration of Nimotop tablets should be continued (dosage as above) to complete the 21 days treatment period.

In patients who develop adverse reactions the dose should be reduced as necessary or the treatment discontinued

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first-pass capacity and a reduced metabolic clearance. The effects and side-effects, e.g. reduction in blood pressure, may be more pronounced in these patients. In such cases the dose should be reduced (depending on the blood pressure) or, if necessary, discontinuation of the treatment should be considered.

Upon co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers a dose adaption may be necessary (see Section 4.5).

Administration:

In general, the tablets should be swallowed whole with a little liquid, with or without food. The interval between successive doses must not be less than 4 hours.

Grapefruit juice is to be avoided (see Section 4.5).

Traumatic subarachnoid haemorrhage:

Not recommended as a positive benefit to risk ratio has not been established (see Section 4.4)

Elderly: There are no special dosage requirements for use in the elderly.

Children: Paediatric dosage has not been established.

4.3 Contraindications

Known hypersensitivity to Nimodipine or any of the excipients.

Nimodipine should not be administered to patients during or within one month of a myocardial infarction or an episode of unstable angina.

The use of nimodipine in combination with rifampicin and the antiepileptic drugs, phenobarbital, phenytoin or carbamazepine is contraindicated as the efficacy of Nimotop tablets could be significantly reduced when concomitantly administered. (See section 4.5 Interaction with other medicinal products and other forms of interaction).

4.4 Special Warnings And Precautions For Use

Nimotop should not be used in patients with traumatic subarachnoid haemorrhage as a positive benefit to risk ratio has not been established and the specific patient groups that might benefit cannot be identified for this indication.

Nimotop tablets should be used with care when cerebral oedema or severely raised intracranial pressure are present. Although treatment with Nimotop has not been shown to be associated with increases in intracranial pressure, close monitoring is recommended in these cases or when the water content of the brain tissue is elevated (generalised cerebral oedema).

Caution is required in patients with hypotension.

Decreased drug clearance may occur in cirrhotic patients receiving Nimotop and, therefore, close monitoring of blood pressure is recommended in these patients.

Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Drugs which are known inhibitors of the cytochrome P450 3A4 system and, therefore, may lead to increased plasma concentrations of nimodipine are macrolide antibiotics (e.g. erythromycin), anti-HIV protease inhibitors (e.g. ritonavir), azole antimycotics (e.g. ketoconazole), the antidepressants nefazodone and fluoxetine, quinupristin/dalfopristin, cimetidine and valproic acid.

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction in the nimodipine dose should be considered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Nimotop tablets should not be administered concomitantly with Nimotop solution.

Drugs that affect nimodipine

Nimodipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine.

The extent as well as the duration of interactions should be taken into account when administering nimodipine together with the following drugs:

The concomitant use of oral nimodipine and rifampicin or cytochrome P450 3A4 system-inducing antiepileptic drugs such as phenobarbital, phenytoin or carbamazepine is contraindicated (see section 4.3 contraindications). The efficacy of Nimotop tablets could be reduced if these drugs are administered concomitantly.

Upon co-administration with the following inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, an adaption in the nimodipine dose should be considered (see section 4.2 Posology and method of administration):

- macrolide antibiotics (e.g. erythromycin)

- anti-HIV protease inhibitors (e.g. ritonavir)

- azole anti-mycotics (e.g. ketoconazole)

- nefazodone.

Although no formal interaction studies have been performed to investigate the potential interaction between nimodipine and these drugs the potential for drug interaction and increased nimodipine plasma concentrations cannot be excluded. (See section 4.4 Special warnings and precautions for use).

Azithromycin, although structurally related to the class of macrolide antibiotics, is void of CYP3A4 inhibition.

Concurrent twice daily administration of 30mg nimodipine and daily administration of 20mg of the antidepressant fluoxetine to elderly patients resulted in an increase in nimodipine plasma levels, a reduction in fluoxetine levels and a trend towards increased norfluoxetine levels. The daily dose used in patients with subarachnoid haemorrhage is four times the daily dose used in this trial, and as a steady state norfluoxetine level was not achieved, the clinical significance of this interaction in the treatment of aneurysmal subarachnoid haemorrhage (aSAH) is uncertain.

Concurrent three times daily administration of 30mg nimodipine and three times daily administration of 10mg of the antidepressant nortriptyline to elderly patients resulted in a slight decrease in nimodipine plasma levels with no effect on nortriptyline plasma levels. The daily dose used in patients with subarachnoid haemorrhage is four times the daily dose used in this trial, thus the clinical significance of this interaction in the treatment of aneurysmal subarachnoid haemorrhage (aSAH) is uncertain.

The simultaneous administration of nimodipine with the anticonvulsant valproic acid or the H2-antagonist cimetidine can lead to an increase in the plasma concentration of nimodipine.

Based on experience with the calcium-antagonist, nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine.

Effects of nimodipine on other drugs

Animal studies have shown that when nimodipine and zidovudine are administered concomitantly, the AUC for zidovudine was increased, and the volume of distribution and clearance rate decreased. The clinical relevance of this interaction is unknown, but since the side-effects profile of zidovudine is known to be dose-related, this interaction should be considered in patients receiving nimodipine and zidovudine concomitantly.

Other types of interaction

Blood pressure lowering drugs

Nimodipine may increase the blood pressure lowering effect of concomitant antihypertensives, such as diuretics, beta-blockers, ACE inhibitors, A1-antagonists, other calcium antagonists, alpha-adrenergic blocking agents, PDE5 inhibitors and alpha-methyldopa. If a combination of this type proves unavoidable particularly careful monitoring of the patient is necessary.

The intake of grapefruit juice is not recommended in combination with nimodipine as it can result in increased plasma nimodipine concentrations due to the inhibition of the oxidative metabolism of dihydropyridines. As a consequence, the blood pressure lowering effect may be increased. This effect may last for at least 4 days after the last ingestion of grapefruit juice.

Interactions shown not to exist

A study examining the effects of 90mg nimodipine (in divided doses) on elderly patients receiving haloperidol did not show evidence of potential interactions. It is unclear whether this study is relevant to use in subarachnoid haemorrhage because of the higher dose of nimodipine used.

Concomitant administration of oral nimodipine and diazepam, digoxin, glibenclamide, indometacin, ranitidine and warfarin did not reveal any potential for mutual interaction.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well controlled studies in pregnant women. Reproductive toxicology studies in animals using oral administration showed no teratogenic effect, although studies in animals have shown reproductive toxicity (see Section 5.3). If nimodipine is to be administered during pregnancy, the benefits and potential risks must be carefully weighed according to the severity of the clinical picture.

Lactation

Nimodipine and its metabolites have been shown to be present in human milk. Nursing mothers are advised not to breast-feed when taking this drug.

In-vitro fertilisation

In single cases of in-vitro fertilisation calcium antagonists have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function.

4.7 Effects On Ability To Drive And Use Machines

In theory, the possibility of the occurrence of the side-effect dizziness may impair the patient's ability to drive or operate machinery.

4.8 Undesirable Effects

The following events have been mainly reported in clinical trials. The following definitions of frequencies are used:

Very common (

Blood and Lymphatic System Disorders

• Thrombocytopenia is uncommon.

Immune System Disorders

• Acute hypersensitivity reactions include uncommonly occurring mild to moderate allergic reactions.

• Associated clinical symptoms related to skin (uncommon rash).

Nervous System Disorders

• Unspecific cerebrovascular symptoms include uncommonly occurring headache.

Cardiac Disorders

• Unspecific cardiac arrhythmias: tachycardia is uncommon and bradycardia is rare.

Vascular Disorders

• Unspecific cardiovascular symptoms such as hypotension and vasodilatation (sweating, flushing and feeling of warmth) are uncommon.

Gastrointestinal Disorders

• Unspecific gastrointestinal and abdominal symptoms include uncommonly occurring nausea.

• Rarely ileus has been reported.

Hepatobiliary Disorders

• Liver reactions include a rarely occurring transient increase in liver enzymes (including an increase in transaminases, alkaline phosphatase and γ-GT).

4.9 Overdose

Symptoms of acute overdosage to be anticipated are marked lowering of the blood pressure, tachycardia, bradycardia and (after oral administration) gastro-intestinal complaints and nausea.

In the event of acute overdosage, treatment with Nimotop must be discontinued immediately. Emergency measures should be governed by the symptoms. Gastric lavage with addition of charcoal should be considered as an emergency therapeutic measure. If there is a marked fall in blood pressure, dopamine or noradrenaline can be administered intravenously. As no specific antidote is known, subsequent treatment for other side effects should be aimed at the most prominent symptoms.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC-Code: C08 CA06

Nimodipine is a calcium channel blocker of the dihydropyridine group with preferential activity on cerebral vessels. Nimodipine increases cerebral perfusion, particularly in poorly perfused areas, by arterial dilatation, an effect which is proportionately greater in smaller than in larger vessels.

Vasoconstrictions provoked in vitro by various vasoactive substances (e.g., serotonin, prostaglandins and histamine) or by blood and blood degradation products can be prevented or reduced by up to 75 % by nimodipine.

5.2 Pharmacokinetic Properties

The intravenous Nimotop solution is 100 % available to the tissues as the peripheral venous blood takes the drug to the lungs and heart and from there to all organs.

After oral ingestion, absorption is rapid. Peak plasma concentrations are observed 30 to 60 minutes following oral administration. Despite high gastrointestinal absorption of nimodipine, the absolute bioavailability is 5 – 15 %, which is attributed to extensive first pass metabolism (about 85 – 95 %).

The distribution volume (Vss, 2 compartment model) for i.v. administration is calculated to be 0.9 – 2.3 l/kg body weight. The total (systemic) clearance is 0.8 – 1.6 l/h/kg. Nimodipine is 97 – 99 % bound to plasma proteins.

The cytochrome P450 3A4 system plays a major role in the metabolic elimination of nimodipine. Nimodipine is eliminated as metabolites, mainly by dehydrogenation of the dihydropyridine ring and oxidative O-demethylation. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups, and glucuronidation as a conjugation reaction are other important metabolic steps. The three primary metabolites occurring in plasma show no or only therapeutically negligible residual activity.

Effects on liver enzymes by induction or inhibition are unknown. In humans the metabolites are excreted about 50% renally and 30% in the bile

For oral administration, the peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg). The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hours. The terminal half-life is 5-10 hours, and is not relevant for establishing the recommended dosing interval for the medicinal product.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenicity and male and female fertility. However, several preclinical findings may be of relevance to the prescribing physician. In chronic repeat dose toxicity studies in dogs, doses of 1 and 2.5 mg/kg/day were shown to be tolerated without adverse effect. However, at the higher dose of 6.25 mg/kg/day significant changes in ECGs were noted due to disturbances in myocardial blood flow, but there was no indication of histopathological damage to the heart. In pregnant rats, doses of 30 mg/kg/day and higher inhibited fetal growth and resulted in reduced fetal weights. At 100 mg/kg/day embryolethality occurred. No evidence of teratogenicity was observed. In rabbits, equivocal evidence of teratogenicity was seen in one study at doses up to 10 mg/kg/day. In two subsequent studies (one at 30 mg/kg/day), these findings were not reproduced. In one peri-postnatal study in rats, mortality and delayed physical development were observed at doses of 10 mg/kg/day and higher. The findings were not confirmed in subsequent studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose, maize starch, povidone, crospovidone, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide E171, iron oxide yellow E172.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 30^OC.

6.5 Nature And Contents Of Container

PP/aluminium blister packs contained in cardboard outer, containing 100 x 30mg tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury, Berkshire

RG14 1JA

Trading as Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0137

9. Date Of First Authorisation/Renewal Of The Authorisation

23 February 1989/23 November 2003

10. Date Of Revision Of The Text

13^th May 2010

Corzide

Pronunciation: BEN-droe-FLOO-me-THYE-a-zide/NAY-doe-lol
Generic Name: Bendroflumethiazide/Nadolol
Brand Name: Corzide

Do not suddenly stop taking Corzide. Sharp chest pain, irregular heartbeat, and sometimes heart attack may occur if you suddenly stop Corzide. The risk may be greater if you have certain types of heart disease. Your doctor should slowly lower your dose over several weeks if you need to stop taking it. This should be done even if you only take Corzide for high blood pressure. Heart disease is common and you may not know you have it. Limit physical activity while you are lowering your dose. If new or worsened chest pain or other heart problems occur, contact your doctor right away. You may need to start taking Corzide again.

Corzide is used for:

Treating high blood pressure.

Corzide is a beta-blocker and diuretic combination. It works by decreasing the force and slowing down the heartbeat, helping the heart beat more regularly and reducing the amount of work the heart has to do. It also increases the elimination of excess fluid, which helps to decrease blood pressure.

Do NOT use Corzide if:

• you are allergic to any ingredient in Corzide or to sulfonamide medicines (eg, glyburide, probenecid, sulfamethoxazole)


• you have uncontrolled heart failure or a very slow and irregular heartbeat (eg, heart block)


• you are unable to urinate


• you have a history of asthma


• you are taking dofetilide or mibefradil

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

Before using Corzide:

Some medical conditions may interact with Corzide. 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 bronchitis, lung disease (eg, chronic obstructive pulmonary disease [COPD]), diabetes, gout, an overactive thyroid, low blood levels of potassium or sodium, heart problems (eg, congestive heart failure[CHF]), blood vessel problems, pheochromocytoma, lupus, liver disease, or kidney problems


• if you are having surgery or receiving anesthesia

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

• Dofetilide or mibefradil because the risk of serious heart side effects may be increased


• Many prescription and nonprescription medicines (eg, used for infections, inflammation, aches and pains, high blood pressure, heart problems, irregular heartbeat, diabetes, depression, mental or mood problems, immune system suppression, allergic reactions, asthma, high cholesterol, seizures), multivitamin products, and herbal or dietary supplements (eg, herbal teas, garlic, ginseng, ginkgo, St. John's wort) may interact with Corzide, increasing the risk of side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Corzide 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 Corzide:

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

• Take Corzide by mouth with or without food.


• Corzide may increase the amount of urine or cause you to urinate more often when you first start taking it. To keep this from disturbing your sleep, try to take your dose before 6 pm.


• If you miss a dose of Corzide, take the missed dose if you remember the same day. Skip the missed dose if you do not remember the same day. Do not take 2 doses at once.

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

Important safety information:

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


• Corzide may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.


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


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


• If you have high blood pressure, do not use nonprescription products that contain stimulants. These products may include diet pills or cold medicines. Contact your doctor if you have any questions or concerns.


• Diabetes patients - Corzide may hide signs of low blood sugar, such as a rapid heartbeat. Be sure to watch for other signs of low blood sugar. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your vision change; give you a headache, chills, or tremors; or make you more hungry. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including blood pressure and heart rate, may be performed while you use Corzide. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Corzide 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 Corzide while you are pregnant. Corzide is found in breast milk. Do not breast feed while taking Corzide.

Possible side effects of Corzide:

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:

Dizziness; lightheadedness; tiredness.

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); chest pain; irregular heartbeat; muscle pain or weakness; swelling of ankles or feet; unusual thirst or fatigue; unusually slow or irregular heartbeat.

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: Corzide 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 coughing; dizziness; drowsiness; fainting; loss of consciousness; low blood pressure; muscular weakness; nausea; seizures; slow heart rate; trouble breathing; upset stomach; vomiting; weakness.

Proper storage of Corzide:

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

General information:

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


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


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


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

This information is a summary only. It does not contain all information about Corzide. 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 Corzide resources

• Corzide Side Effects (in more detail)
• Corzide Use in Pregnancy & Breastfeeding
• Corzide Drug Interactions
• Corzide Support Group
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