Download PLR Content Marketing Grenada: March 2012

Friday, March 30, 2012

Eporatio 30,000 IU

1. Name Of The Medicinal Product

Eporatio 30,000 IU/1 ml solution for injection in pre

2. Qualitative And Quantitative Composition

One pre-filled syringe contains 30,000 international units (IU) (250 µg) epoetin theta in 1 ml solution for injection corresponding to 30,000 IU (250 µg) epoetin theta per ml.

Epoetin theta (recombinant human erythropoietin) is produced in Chinese Hamster Ovary Cells (CHO

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection) in pre

The solution is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of symptomatic anaemia associated with chronic renal failure in adult patients.

- Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

4.2 Posology And Method Of Administration

Special requirements

Epoetin theta treatment should be initiated by physicians experienced in the above-mentioned indications.

Routes of administration

The solution can be administered subcutaneously (SC) or intravenously (IV). Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. Epoetin theta should be administered by the subcutaneous route to cancer patients with non

Posology

Symptomatic anaemia associated with chronic renal failure

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. Epoetin theta should be administered either subcutaneously or intravenously in order to increase haemoglobin level to not greater than 12 g/dl (7.45 mmol/l).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment if haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.24 mmol/l) over a four week period should be avoided. If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin value exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. It is recommended that haemoglobin be monitored every two weeks until levels have stabilised and periodically thereafter. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25% below the previously administered dose.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the increase in haemoglobin and the target haemoglobin value should be determined individually taking into account the clinical picture.

Treatment with epoetin theta is divided into two stages.

Correction phase

Subcutaneous administration: The initial posology is 20 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 40 IU/kg, 3 times per week, if the increase in haemoglobin is not adequate (< 1 g/dl [0.62 mmol/l] within 4 weeks). Further increases of 25% of the previous dose may be made at monthly intervals until the individual target haemoglobin level is obtained.

Intravenous administration: The initial posology is 40 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 80 IU/kg, 3 times per week, and by further increases of 25% of the previous dose at monthly intervals, if needed.

For both routes of administration, the maximum dose should not exceed 700 IU/kg body weight per week.

Maintenance phase

The dose should be adjusted as necessary to maintain the individual target haemoglobin level between 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l), whereby a haemoglobin level of 12 g/dl (7.45 mmol/l) should not be exceeded. If a dose adjustment is required to maintain the desired haemoglobin level, it is recommended that the dose be adjusted by approximately 25%.

Subcutaneous administration: The weekly dose can be given as one injection per week or three times per week.

Intravenous administration: Patients who are stable on a three times weekly dosing regimen may be switched to twice-weekly administration.

If the frequency of administration is changed, haemoglobin level should be monitored closely and dose adjustments may be necessary.

The maximum dose should not exceed 700 IU/kg body weight per week.

If epoetin theta is substituted for another epoetin, haemoglobin level should be monitored closely and the same route of administration should be used.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Epoetin theta should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration

The recommended initial dose is 20,000 IU, independent of bodyweight, given once-weekly. If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l) a doubling of the weekly dose to 40,000 IU should be considered. If, after an additional 4 weeks of therapy, the haemoglobin increase is still insufficient an increase of the weekly dose to 60,000 IU should be considered.

The maximum dose should not exceed 60,000 IU per week.

If, after 12 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin level exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. Treatment with epoetin theta should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.07 mmol/l). Therapy should be reinitiated at approximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.45 mmol/l) or below.

Therapy should be continued up to 4 weeks after the end of chemotherapy.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Special populations

Paediatric patients

There is no experience in children and adolescents.

Method of administration

The solution can be administered subcutaneously or intravenously. Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. In cancer patients with non

Subcutaneous injections should be given into the abdomen, arm or thigh.

Eporatio is supplied in a single use pre-filled syringe. The solution should be visually inspected prior to use. Only clear, colourless solutions without particles should be used. The solution for injection should not be shaken. It should be allowed to reach a comfortable temperature (15 °C

Eporatio must not be mixed with other medicinal products (see section 6.2).

The injection sites should be rotated and the injection performed slowly to avoid discomfort at the site of injection.

4.3 Contraindications

- Hypersensitivity to the active substance, other epoetins and derivatives or to any of the excipients.

- Uncontrolled hypertension.

4.4 Special Warnings And Precautions For Use

General

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron status has to be evaluated for all patients prior to and during treatment.

Non-response to therapy with epoetin theta should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B₁₂ reduce the effectiveness of epoetins and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, aluminium intoxication, underlying haematological diseases or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation.

Pure red cell aplasia (PRCA)

If typical causes of non-response are excluded, and the patient has a sudden drop in haemoglobin associated with reticulocytopenia, an examination of anti-erythropoietin antibodies and the bone marrow for diagnosis of pure red cell aplasia should be considered. Discontinuation of treatment with epoetin theta should be taken into account.

PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy. These antibodies have been shown to cross-react with all epoetins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to epoetin theta (see section 4.8).

Hypertension

Patients on epoetin theta therapy can experience an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase.

Therefore, in patients treated with epoetin theta, special care should be taken to monitor closely and control blood pressure. Blood pressure should be controlled adequately before initiation and during therapy to avoid acute complications, such as hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke), which may also occur in individual patients with otherwise normal or low blood pressure. If these reactions occur, they require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden sharp migraine-like headaches as a possible warning signal.

Increases in blood pressure may require treatment with antihypertensive medicinal products or a dose increase of existing antihypertensive medicinal products. In addition, a reduction of the administered dose of epoetin theta needs to be considered. If blood pressure values remain high, temporary interruption of epoetin theta therapy may be required. Once hypertension has been controlled with more intensified therapy, epoetin theta therapy should be re-started at a reduced dose.

Misuse

Misuse of epoetin theta by healthy persons may lead to an excessive increase in haemoglobin and haematocrit. This may be associated with life-threatening cardiovascular complications.

Special populations

Due to limited experience, the efficacy and safety of epoetin theta could not be assessed in patients with impaired liver function or homozygous sickle cell anaemia.

In clinical trials, patients over 75 years of age had a higher incidence of serious and severe adverse events irrespective of a causal relationship to treatment with epoetin theta. Furthermore, deaths were more frequent in this patient group compared to younger patients.

Laboratory monitoring

It is recommended that haemoglobin measurement, a complete blood count and platelet count be performed regularly.

Symptomatic anaemia associated with chronic renal failure

The use of epoetin theta in nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible accelerated progression of renal failure cannot be ruled out with certainty.

During haemodialysis, patients treated with epoetin theta may require increased anticoagulation treatment to prevent clotting of the arterio-venous shunt.

In patients with chronic renal failure, the maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when epoetins were administered to target a haemoglobin level in excess of 12 g/dl (7.45 mmol/l). Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when the haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of any type of malignancy (see section 5.1).

In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer. In controlled clinical studies, use of epoetins has shown:

	- shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin level in excess of 14 g/dl (8.69 mmol/l),
	- shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin value of 12
	- increased risk of death when administered to target a haemoglobin value of 12 g/dl (7.45 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy.

Epoetins are not indicated for use in this patient population.

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage, the degree of anaemia, life

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 'sodium-free'.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

For epoetin theta no clinical data on exposed pregnancies are available. Animal studies with other epoetins do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

It is unknown whether epoetin theta is excreted in human breast milk, but data in neonates show no absorption or pharmacological activity of erythropoietin when given together with breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin theta should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin theta therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

Epoetin theta has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The safety of epoetin theta has been evaluated based on results from clinical studies including 972 patients.

Approximately 9% of patients can be expected to experience an adverse reaction. The most frequent undesirable effects are hypertension, influenza-like illness and headache.

Adverse reactions listed below are classified according to System Organ Class. Frequency groupings are defined according to the following convention:

Very common:
Common:
Uncommon:
Rare:
Very rare:	< 1/10,000;
Not known:	cannot be estimated from the available data.

System organ class	Adverse reaction	Frequency
Symptomatic anaemia associated with chronic renal failure	Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy
Blood and lymphatic system disorders	Thromboembolic events	—	Not known
Shunt thrombosis	Common	—
Immune system disorders	Hypersensitivity reactions	Not known
Nervous system disorders	Headache	Common
Vascular disorders	Hypertension	Common
Hypertensive crisis	Common	—
Skin and subcutaneous tissue disorders	Skin reactions	Common
Musculoskeletal and connective tissue disorders	Arthralgia	—	Common
General disorders and administration site conditions	Influenza-like illness	Common

Shunt thrombosis may occur, especially in patients who have a tendency to hypotension or whose arterio-venous fistulae exhibit complications (e.g. stenoses, aneurisms) (see section 4.4).

One of the most frequent adverse reactions during treatment with epoetin theta is an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase. Hypertension occurs in chronic renal failure patients more often during the correction phase than during the maintenance phase. Hypertension can be treated with appropriate medicinal products (see section 4.4).

Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke) may also occur in individual patients with otherwise normal or low blood pressure (see section 4.4).

Skin reactions such as rash, pruritus or injection site reactions may occur.

Symptoms of influenza-like illness such as fever, chills and asthenic conditions have been reported.

Certain adverse reactions have not yet been observed with epoetin theta, but are generally accepted as being attributable to epoetins:

In isolated cases in patients with chronic renal failure, neutralising anti-erythropoietin antibody-mediated PRCA associated with therapy with other epoetins has been reported. If PRCA is diagnosed, therapy with epoetin theta must be discontinued and patients should not be switched to another recombinant epoetin (see section 4.4).

4.9 Overdose

The therapeutic margin of epoetin theta is very wide. In the case of overdose, polycythaemia can occur. In the event of polycythaemia, epoetin theta should be temporarily withheld.

If severe polycythaemia occurs, conventional methods (phlebotomy) may be indicated to reduce the haemoglobin level.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other anti-anaemic preparations, ATC code: B03XA01

Mechanism of action

Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor cells in the bone marrow. It acts as a mitosis-stimulating factor and differentiation hormone. The production of erythropoietin primarily occurs in and is regulated by the kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is impaired in patients with chronic renal failure and the primary cause of their anaemia is erythropoietin deficiency. In patients with cancer receiving chemotherapy the aetiology of anaemia is multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid progenitor cells to endogenous erythropoietin both contribute significantly towards their anaemia.

Epoetin theta is identical in its amino acid sequence and similar in its carbohydrate composition (glycosylation) to endogenous human erythropoietin.

Preclinical efficacy

The biological efficacy of epoetin theta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (mice, rats, dogs). After administration of epoetin theta, the number of erythrocytes, the haematocrit values and reticulocyte counts increase.

Clinical efficacy and safety

Symptomatic anaemia associated chronic renal failure

Data from correction phase studies in 284 chronic renal failure patients show that the haemoglobin response rates (defined as haemoglobin levels above 11 g/dl at two consecutive measurements) in the epoetin theta group (88.4% and 89.4% in studies in patients on dialysis and not yet undergoing dialysis, respectively) were comparable to epoetin beta (86.2% and 81.0%, respectively). The median time to response was similar in the treatment groups with 56 days in haemodialysis patients and 49 days in patients not yet undergoing dialysis.

Two randomised controlled studies were conducted in 270 haemodialysis patients and 288 patients not yet undergoing dialysis, who were on stable treatment with epoetin beta. Patients were randomised to continue their current treatment or to be converted to epoetin theta (same dose as epoetin beta) in order to maintain their haemoglobin levels. During the evaluation period (weeks 15 to 26), the mean and median level of haemoglobin in patients treated with epoetin theta was virtually identical to their baseline haemoglobin level. In these two studies, 180 haemodialysis patients and 193 patients not undergoing dialysis were switched from maintenance phase treatment with epoetin beta to treatment with epoetin theta for a period of six months showing stable haemoglobin values and a similar safety profile as epoetin beta. In the clinical studies, patients not yet undergoing dialysis (subcutaneous administration) discontinued the study more frequently than haemodialysis patients (intravenous administration) as they had to terminate the study when starting dialysis.

In two long-term studies, the efficacy of epoetin theta was evaluated in 124 haemodialysis patients and 289 patients not yet undergoing dialysis. The haemoglobin levels remained within the desired target range and epoetin theta was well tolerated over a period of up to 15 months.

In the clinical studies, pre-dialysis patients were treated once-weekly with epoetin theta, 174 patients in the maintenance phase study and 111 patients in the long-term study.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

409 cancer patients receiving chemotherapy were included in two prospective, randomised double

Effect on tumour growth

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. The target haemoglobin concentration in two studies was> 13 g/dl; in the remaining three studies it was 12

Data from three placebo-controlled clinical studies in 586 anaemic cancer patients conducted with epoetin theta, showed no negative effect of epoetin theta on survival. During the studies, mortality was lower in the epoetin theta group (6.9%) compared to placebo (10.3%).

A systematic review has also been performed involving more than 9,000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.08 in favour of controls (95% CI: 0.99, 1.18; 42 trials and 8,167 patients). An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6,769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence to suggest that there may be significant harm to patients with cancer who are treated with recombinant human erythropoietin. The extent to which these outcomes might apply to the administration of recombinant human erythropoietin to patients with cancer, treated with chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients with these characteristics were included in the data reviewed.

5.2 Pharmacokinetic Properties

General

The pharmacokinetics of epoetin theta have been examined in healthy volunteers, in patients with chronic renal failure and in cancer patients receiving chemotherapy. The pharmacokinetics of epoetin theta are independent of age or gender.

Subcutaneous administration

Following subcutaneous injection of 40 IU/kg body weight epoetin theta at three different sites (upper arm, abdomen, thigh) in healthy volunteers, similar plasma level profiles were observed. The extent of absorption (AUC) was slightly greater after injection in the abdomen in comparison to the other sites. The maximum concentration is reached after an average of 10 to 14 hours and the average terminal half-life ranges from approximately 22 to 41 hours.

Average bioavailability of epoetin theta after subcutaneous administration is approximately 31% compared with intravenous administration.

In pre-dialysis patients with chronic renal failure following subcutaneous injection of 40 IU/kg body weight, the protracted absorption results in a concentration plateau, whereby the maximum concentration is reached after an average of approximately 14 hours. The terminal half-life is higher than after intravenous administration, with an average of 25 hours after single dosing and 34 hours in steady state after repeated dosing three times weekly, without leading to an accumulation of epoetin theta.

In cancer patients receiving chemotherapy, after repeated subcutaneous administration of 20,000 IU epoetin theta once-weekly, the terminal half-life is 29 hours after the first dose and 28 hours in steady state. No accumulation of epoetin theta was observed.

Intravenous administration

In patients with chronic renal failure undergoing haemodialysis, the elimination half-life of epoetin theta is 6 hours after single dosing and 4 hours in steady state after repeated intravenous administration of 40 IU/kg body weight epoetin theta three times weekly. No accumulation of epoetin theta was observed. Following intravenous administration, the volume of distribution approximates to total blood volume.

5.3 Preclinical Safety Data

Non-clinical data with epoetin theta reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.

Non-clinical data with other epoetins reveal no special hazard for humans based on conventional studies of genotoxicity and toxicity to reproduction.

In reproductive toxicity studies performed with other epoetins, effects interpreted as being secondary to decreased maternal body weight were observed at doses sufficiently in excess to the recommended human dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Polysorbate 20

Trometamol

Hydrochloric acid (6 M) (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

For the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at a temperature not above 25 °C for a single period of up to 7 days without exceeding the expiry date. Once removed from the refrigerator, the medicinal product must be used within this period or disposed of.

6.5 Nature And Contents Of Container

1 ml of solution in a pre-filled syringe (type I glass) with a tip cap (bromobutyl rubber), a plunger stopper (teflonised chlorobutyl rubber), an injection needle (stainless steel) and with or without a pre

Pack sizes of 1, 4 and 6 pre-filled syringes with or without safety device.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The pre

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

ratiopharm GmbH

Graf-Arco-Straße 3

89079 Ulm

Germany

info@ratiopharm.de

8. Marketing Authorisation Number(S)

EMEA/H/C/0010350000/25

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29 October 2009

10. Date Of Revision Of The Text

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Thursday, March 22, 2012

Multaq

Generic Name: Dronedarone Hydrochloride
Class: Class III Antiarrhythmics
VA Class: CV300
Chemical Name: N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]-methanesulfonamide monohydrochloride
Molecular Formula: C₃₁H₄₄N₂O₅S•HCl
CAS Number: 141625-93-6

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals that it is reviewing data from a clinical trial that evaluated the effects of the antiarrhythmic drug dronedarone (Multaq) in patients with permanent atrial fibrillation. The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving dronedarone compared to patients taking a placebo. FDA is evaluating whether and how the preliminary results of the PALLAS study apply to patients taking dronedarone for paroxysmal or persistent atrial fibrillation or atrial flutter. The PALLAS study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated. FDA will update the public when more information is available.

BACKGROUND: Dronedarone is approved for use to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted.

RECOMMENDATION: At this time, patients taking dronedarone should talk to their healthcare professional about whether they should continue to take dronedarone for non-permanent atrial fibrillation. Patients should not stop taking dronedarone without talking to a healthcare professional. Healthcare professionals should not prescribe dronedarone to patients with permanent atrial fibrillation. See the Data Summary in the Drug Safety Communication for additional details at: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for dronedarone hydrochloride to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of dronedarone hydrochloride and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Heart Failure under Cautions.)

In the ANDROMEDA study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms, dronedarone therapy was associated with a greater than twofold increase in mortality rate relative to placebo;¹ ⁴ do not use dronedarone in such patients.¹

Introduction

Class III antiarrhythmic agent;⁵ ⁶ ⁷ also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.¹ ⁵ ⁶ ⁸

Uses for Multaq

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Supraventricular Tachyarrhythmias

Reduction of risk of hospitalization for cardiovascular events in patients with paroxysmal or persistent atrial fibrillation or atrial flutter who have had a recent episode of atrial fibrillation/flutter and who have associated cardiovascular risk factors (i.e., >70 years of age, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm, or left ventricular ejection fraction <40%); used in such patients who are in sinus rhythm or who will undergo cardioversion.¹ ⁹ (See Boxed Warningand also see Contraindications and see Heart Failure under Cautions.)

Less effective than amiodarone in preventing recurrence of atrial fibrillation but appears to have an improved safety profile (based on short-term data).⁴ ⁵ ⁸ ⁹ ¹⁴ ¹⁶ ¹⁹ ²⁴ Long-term data and experience needed to elucidate relative safety and tolerability of dronedarone versus amiodarone because of some late-onset adverse effects of amiodarone (e.g., pulmonary toxicity).⁶ ⁸ ¹⁴ ¹⁶ ¹⁸ ¹⁹

Efficacy of retreatment with dronedarone in patients who relapse after initial successful treatment or in those who fail therapy with amiodarone not established.¹⁷ ²¹

Individualize treatment of atrial fibrillation/flutter based on relative benefits and risks of various therapies (e.g., rhythm versus rate control, nondrug therapies such as ablation and pacemaker implantation), patient age, and patient preference and tolerance of the arrhythmia.¹⁵ ¹⁷ ¹⁸ ²⁰ ²¹ ²² ²³ ²⁴ ²⁶

Multaq Dosage and Administration

General

Risk Evaluation and Mitigation Strategy

FDA-required Risk Evaluation and Mitigation Strategy (REMS) implemented to assist healthcare professionals with identification of appropriate patients to receive dronedarone and ensure safe use while minimizing risk.¹⁰ ¹¹ ¹²

Goals of program (mPACT: MULTAQ Partnership for Appropriate Care and Treatment) are to educate prescribers about the increased risk of mortality associated with use of dronedarone in patients with NYHA class IV heart failure and in those who have NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic, and to prevent use of the drug in such patients.¹² Also designed to inform patients about serious risks associated with dronedarone, including an increased rate of mortality in patients with severe, unstable heart failure.¹² (See Contraindicationsand also see Heart Failure under Cautions.) REMS program consists of educational materials for healthcare professionals and patients, including a medication guide to be dispensed with every dronedarone prescription.¹ ¹⁰ ¹¹ ¹²

For additional information, consult the Multaq website at .¹⁰

Administration

Oral Administration

Administer orally twice daily with morning and evening meals (to enhance bioavailability).¹ (See Food under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as dronedarone hydrochloride; dosage expressed in terms of dronedarone.¹

Adults

Supraventricular Tachyarrhythmias

Oral

Reduction of risk of hospitalization due to cardiovascular events in selected patients with paroxysmal or persistent atrial fibrillation/flutter: 400 mg twice daily with morning and evening meals.¹

Must discontinue class I or III antiarrhythmic agents and drugs that are potent inhibitors of cytochrome P450 (CYP) isoenzyme 3A prior to initiating dronedarone.¹ ⁹ (See Contraindications under Cautions and also see Interactions.)

Special Populations

The manufacturer states that no dosage other than 400 mg twice daily of dronedarone is recommended for any population at this time.⁹

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment.¹ Contraindicated in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.¹ (See Renal Impairment under Cautions.)

Cautions for Multaq

Contraindications

NYHA Class IV heart failure or NYHA Class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warning and also see Heart Failure under Cautions.)

Second- or third-degree AV block or sick sinus syndrome (except in patients with a functioning pacemaker).¹

Bradycardia (<50 beats/minute).¹

QT interval corrected for rate, Bazett’s formula (QT_c) of ≥500 msec or PR interval >280 msec.¹ ⁹ (See Prolongation of QT Interval under Cautions.)

Concomitant use of potent inhibitors of CYP3A (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole).¹ (See Drugs Affecting Hepatic Microsomal Enzymes and also see Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Concomitant use with drugs or herbal supplements that prolong the QT interval and may increase the risk of torsades de pointes (e.g., class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides).¹ ⁹ (See Drugs that Prolong the QT Interval under Interactions.)

Severe hepatic impairment.¹ (See Hepatic Impairment and also see Severe Hepatic Injury under Cautions.)

Women who are or may become pregnant.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Nursing women.¹

Warnings/Precautions

Heart Failure

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

In ANDROMEDA study, greater than twofold increase relative to placebo in rate of mortality in dronedarone-treated patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms; do not use dronedarone in such patients.¹ ⁴

Limited clinical experience available in patients with atrial fibrillation/flutter who develop worsening heart failure during therapy with dronedarone.¹ Worsening heart failure complicated by multiorgan dysfunction (e.g., acute renal and hepatic failure) in the setting of dronedarone initiation reported during postmarketing surveillance in at least one patient with atrial fibrillation and history of NYHA class III-IV heart failure and multiple recent hospitalizations for heart failure.²⁶

If heart failure develops or worsens, consider interrupting or discontinuing therapy.¹

Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warningand also see Contraindications under Cautions.)

Severe Hepatic Injury

Severe hepatic injury reported rarely with dronedarone therapy.²⁸ Acute hepatic failure requiring liver transplantation reported in at least 2 patients; in both cases, explanted liver showed evidence of extensive hepatocellular necrosis.²⁸

Consider periodic monitoring of serum hepatic enzymes, especially during first 6 months of therapy.²⁸ If hepatic injury suspected (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching), discontinue dronedarone therapy promptly and assess serum hepatic enzymes and bilirubin; initiate appropriate therapy if hepatic injury found.²⁸ Do not reinitiate dronedarone therapy in patients who experience hepatic injury without another explanation for such injury.²⁸

Hypokalemia and Hypomagnesemia

Possible hypokalemia and hypomagnesemia with concomitant use of potassium-depleting diuretics.¹ Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy.¹ ⁹ ²⁴

Prolongation of QT Interval

Moderate prolongation of QT_c interval reported; QT_c interval increased by an average of about 10 msec, however, greater prolongation reported.¹ Discontinue dronedarone if QT_c interval is ≥500 msec.¹ (See Contraindications under Cautions.)

Increased Serum Creatinine Concentrations

Increase in S_cr of about 0.1 mg/dL reported following initiation of drug; however, may not necessarily indicate decline in renal function.¹ ² ⁴ ⁵ ¹³ ¹⁶ Increase in S_cr and decrease in Cl_cr by about 10–15 or 18%, respectively, observed in clinical studies in healthy individuals and patients receiving the drug; however, no clinically important change in glomerular filtration rate, renal plasma flow or electrolyte exchanges, or any structural renal damage reported.¹ ² ³ ⁴ ¹³ Change in S_cr may result from a specific partial inhibition of tubular organic cation transporters and inhibition of tubular secretion of creatinine by dronedarone.¹ ⁵ ¹³ ¹⁶

Increases in S_cr appear to have a rapid onset, reach a plateau after 7 days, and are reversible following discontinuance of the drug.¹ ¹³ If an increase in the S_cr occurs and plateaus, use this increased value as the patient’s new baseline S_cr.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.¹

Avoid pregnancy during therapy; women of childbearing potential (i.e., premenopausal women who have not undergone hysterectomy or oophorectomy) must use effective contraception.¹ If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.¹ (See Advice to Patients.)

Contraindicated in women who are or may become pregnant.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Lactation

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into milk in humans.¹ Discontinue nursing or the drug.¹ Contraindicated in nursing women.¹

Pediatric Use

Safety and efficacy not established in children or adolescents <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy relative to those in younger adults.¹ (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Not studied in patients with severe hepatic impairment; limited clinical experience available in patients with moderate hepatic impairment.¹ Severe liver injury reported rarely with dronedarone therapy.²⁸ (See Severe Hepatic Injury under Cautions.) Contraindicated in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required because dronedarone undergoes minimal renal excretion.¹ (See Special Populations and also see Elimination Route under Pharmacokinetics.)

Common Adverse Effects

Increased S_cr (increase of ≥10% five days after initiation of drug),¹ prolonged QT_c interval (>450 msec [males] or >470 msec [females]),¹ diarrhea,¹ ² ¹⁴ asthenia,¹ nausea,¹ ² skin reactions (e.g., rash [generalized, macular, maculo-papular, erythematous], pruritus, eczema, dermatitis, allergic dermatitis),¹ ² abdominal pain,¹ bradycardia,¹ ² vomiting,¹ dyspepsia.¹ (See Contraindications and see Prolongation of QT Interval and also see Increased Serum Creatinine Concentrations under Cautions.)

Interactions for Multaq

Metabolized mainly by CYP isoenzyme 3A.¹

Moderate inhibitor of CYP isoenzymes 3A and 2D6; does not appear to substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2C8, or 2B6.¹ May inhibit P-glycoprotein transport system.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Pharmacokinetic interaction (increased exposure to and peak plasma concentrations of dronedarone).¹ Concomitant use contraindicated.¹

Inhibitors of CYP3A: Potential pharmacokinetic interaction (altered concentrations of dronedarone).¹

Inducers of CYP3A: Potential pharmacokinetic interaction (substantially decreased exposure to dronedarone).¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (possible increased plasma concentrations of the CYP3A substrate).¹ ⁹ ²⁵ Monitor plasma concentrations and appropriately adjust dosage of CYP3A substrates with a narrow therapeutic index when administered orally.¹ ⁹ Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by CYP3A4.²⁵

Substrates of CYP2D6: Potential pharmacokinetic interaction (possible increased exposure to the CYP2D6 substrate).¹

Drugs that Prolong the QT Interval

Pharmacologic interaction (potential risk of torsades de pointes-type ventricular tachycardia) with drugs or herbal supplements that prolong the QT interval; concomitant use contraindicated.¹ ⁹ (See Contraindications under Cautions.)

Drugs Affected by the P-glycoprotein Transport System

Potential pharmacokinetic interaction (increased exposure to substrates of P-glycoprotein transport system [e.g., digoxin] expected) when used concomitantly with dronedarone.¹ Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by the P-glycoprotein transport system.²⁵

Specific Drugs and Food

Drug	Interaction	Comments
Antiarrhythmic agents, class I or III (e.g., amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine, sotalol)	Potential risk of torsades de pointes-type ventricular tachycardia¹	Concomitant use contraindicated¹
Anticoagulants, oral (e.g., warfarin)	Increased exposure to S-warfarin in healthy individuals; no change in exposure to R-warfarin or clinically important increases in the INR¹ No excess risk of bleeding observed with concomitant use of dronedarone and oral anticoagulants in patients with atrial fibrillation/flutter¹	Monitor INR according to manufacturers’ labeling for warfarin¹
Antidepressants, SSRI	Possible increased exposure to SSRI¹
Antidepressants, tricyclic	Potential risk of torsades de pointes-type ventricular tachycardia¹ Possible increased exposure to tricyclic antidepressants¹	Concomitant use contraindicated¹
β-Adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased incidence of bradycardia observed¹ Increased exposure to metoprolol and propranolol; possible increased exposure to other β-adrenergic blocking agents that are CYP2D6 substrates¹	If used with β-adrenergic blocking agents, use lower initial dosage of the β-adrenergic blocking agent and increase dosage of β-adrenergic blocker only if well tolerated as documented by ECG¹ ⁹
Calcium-channel blocking agents (e.g., diltiazem, nifedipine, verapamil)	Calcium-channel blocking agents with depressant effects on the sinus and AV nodes may potentiate the conduction effects of dronedarone¹ Dronedarone increases exposure to calcium-channel blocking agents (verapamil, diltiazem, nifedipine); verapamil and diltiazem increase exposure to dronedarone¹	If used with calcium-channel blocking agents, use lower initial dosage of the calcium-channel blocking agent and increase dosage of calcium-channel blocker only if well tolerated as documented by ECG¹ ⁹
Carbamazepine	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Cyclosporine	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Digoxin	Possible potentiation of electrophysiologic effects of dronedarone (e.g., decreased AV node conduction)¹ Increased exposure to digoxin and increased digoxin concentrations¹ Increased incidence of GI disorders observed¹	When initiating dronedarone therapy, reassess need for continued digoxin therapy; discontinue digoxin or reduce digoxin dosage by 50%¹ Monitor serum digoxin concentrations; close observation for signs of digoxin toxicity recommended¹
Grapefruit juice	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Avoid grapefruit juice during dronedarone therapy¹ ⁹
HMG-CoA reductase inhibitors (statins)	Increased exposure to simvastatin and simvastatin acid¹	Consult manufacturer’s labeling for the respective statin for specific recommendations regarding concomitant use with CYP3A or P-glycoprotein transport system inhibitors such as dronedarone¹
Itraconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Ketoconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Losartan	No drug interaction observed¹
Macrolides	Clarithromycin, telithromycin: Increase exposure to and peak plasma concentrations of dronedarone¹ Certain oral macrolides: Potential risk of torsades de pointes-type ventricular tachycardia¹	Clarithromycin, telithromycin, and certain oral macrolides: Concomitant use with dronedarone contraindicated¹
Nefazodone	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Oral contraceptives	No decreases in ethinyl estradiol or levonorgestrel concentrations observed in healthy individuals¹
Pantoprazole	No clinically important effect on the pharmacokinetics of dronedarone¹
Phenobarbital	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Phenothiazines	Potential risk of torsades de pointes-type ventricular tachycardia¹	Concomitant use contraindicated¹
Phenytoin	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Potassium-depleting diuretics	Possible hypokalemia or hypomagnesemia¹	Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy¹
Rifampin	Decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Ritonavir	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
St. John’s wort	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Sirolimus	Possible increased plasma concentrations of sirolimus;¹ initiation of dronedarone therapy in one patient receiving sirolimus post-kidney transplantation resulted in a threefold increase in trough sirolimus concentrations from baseline²⁵	Monitor plasma concentrations of sirolimus and adjust dosage appropriately when used concomitantly with dronedarone¹ Some clinicians recommend avoidance of concurrent use of sirolimus and dronedarone when possible. If concurrent administration cannot be avoided, a 50–75% reduction in sirolimus dosage prior to dronedarone initiation has been suggested; monitor trough sirolimus concentrations regularly (possibly even daily) during titration phase²⁵
Tacrolimus	Possible increased plasma concentrations of tacrolimus¹	Monitor plasma concentrations of tacrolimus and adjust dosage appropriately during concomitant use¹
Theophylline	No apparent increase in steady-state exposure to theophylline¹
Voriconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹

Multaq Pharmacokinetics

Absorption and Distribution

Bioavailability

Low systemic bioavailability; undergoes first-pass metabolism.¹ Absolute bioavailability about 4% when administered without food.¹

Steady-state concentrations achieved within 4–8 days following repeated oral administration of dronedarone 400 mg twice daily.¹

Food

Food increases bioavailability; bioavailability approximately 15% when administered with a high-fat meal.¹

Peak plasma concentrations of dronedarone and N-debutyl metabolite reached within 3–6 hours following oral administration with food.¹

Special Populations

Exposure to dronedarone increased by 23% in patients ≥65 years of age compared with that in younger adults.¹ (See Geriatric Use under Cautions.)

Mean exposure to dronedarone increased by 1.3-fold in patients with moderate hepatic impairment compared with individuals with normal hepatic function; mean exposure to N-debutyl metabolite decreased by about 50%.¹ (See Hepatic Impairment under Cautions.)

Pharmacokinetics not studied in patients with severe hepatic impairment; contraindicated in such patients.¹

No apparent differences in pharmacokinetics observed in healthy individuals with mild or moderate renal impairment versus those with normal renal function, or in patients with atrial fibrillation and mild to severe renal impairment versus those with normal renal function.¹ ⁹ (See Renal Impairment under Cautions.)

Exposure to dronedarone averages 30% higher in women than in men.¹

Pharmacokinetic differences related to race not formally studied.¹ However, based on a cross-study comparison, exposure to dronedarone twofold higher in Asian men (of Japanese ancestry) than in Caucasian men following single-dose administration of dronedarone 400 mg.¹

Distribution

Extent

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Dronedarone and N-debutyl metabolite are >98% bound to plasma proteins (mainly albumin); binding not saturable.¹

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A.¹

Initial metabolic pathway includes N-debutylation to form active N-debutyl metabolite, oxidative deamination to form inactive propanoic acid metabolite, and direct oxidation.¹ Metabolites further metabolized to >30 uncharacterized metabolites.¹ N-debutyl metabolite exhibits pharmacodynamic activity; only up to one-third as potent as dronedarone.¹

Elimination Route

Excreted in urine (6%) and in feces (84%) mainly as metabolites; no unchanged drug excreted in urine.¹

Half-life

13–19 hours following IV administration.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Mechanism of antiarrhythmic action not fully elucidated; exact contribution of activities in each of the 4 Vaughan-Williams antiarrhythmic classes to the clinical effect of the drug unknown.¹ ⁵

Benzofuran derivative structurally related to amiodarone, but with structural modifications that include removal of the iodine group and addition of a methane-sulfonyl group.¹ ² ³ ⁵ ⁶ ⁷ ⁸ ¹⁶

Removal of the iodine group intended to reduce risk of nontarget organ (e.g., thyroid, pulmonary) adverse effects associated with amiodarone therapy; addition of the methane-sulfonyl group aimed at reducing lipophilicity, decreasing risk of neurotoxic adverse effects, and shortening half-life of dronedarone.² ³ ⁵ ⁶ ⁸ ¹⁶

Electrophysiologic profile similar to amiodarone, but with different relative effects on individual ion channels.² ³ ⁴ ⁵ ⁶

Prolongs action potential duration (APD) mainly by inhibition of potassium channels, including transmembrane delayed rectifier, ultrarapid delayed rectifier, inward rectifier, and transient outward potassium currents.⁵ ⁶

Inhibits sodium currents (at rapid pacing rates), calcium channels and slow L-type calcium currents, and demonstrates noncompetitive, antiadrenergic (α- and β-blocking) activity.⁵ ⁶ ⁸ ¹⁶

Prolongs PR interval and slows sinus rate by prolonging atrial and ventricular refractory periods.¹ ⁸

Prolongs RR and QT intervals.⁵ ⁶

Produces a dose-dependent increase in PR interval and a moderate prolongation of the QT_c interval similar to amiodarone.¹ ⁵ ⁸

Advice to Patients

Importance of instructing patients to carefully read the manufacturer’s patient information (medication guide) before initiating therapy and each time the prescription is refilled.¹

Importance of informing clinician if signs or symptoms of heart failure (e.g., weight gain, dependent edema, increasing shortness of breath) occur.¹

Importance of advising patients receiving dronedarone to immediately report symptoms suggesting hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching).²⁸

Importance of taking dronedarone with a meal.¹

Importance of advising patients to avoid grapefruit juice while taking dronedarone.¹ (See Specific Drugs and Food under Interactions.)

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and breast-feeding during dronedarone therapy.¹ ⁹ Necessity of advising women of childbearing potential to use an effective method of contraception while receiving therapy and importance of advising these patients regarding appropriate contraceptive choices (taking into consideration their underlying medical conditions and lifestyle preferences).¹ If pregnancy occurs, advise patient of risk to the fetus.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., heart failure, rhythm disturbance other than atrial fibrillation/flutter, uncorrected hypokalemia).¹

Importance of advising patients that if a dose of dronedarone is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.¹

Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dronedarone Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	400 mg (of dronedarone)	Multaq	Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Multaq 400MG Tablets (SANOFI-AVENTIS U.S.): 60/$276.00 or 180/$766.01

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Multaq (dronedarone hydrochloride) tablets prescribing information. Bridgewater, NJ; 2009 Jul.

2. Hohnloser SH, Crijns HJ, van Eickels M et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009; 360:668-78. [PubMed 19213680]

3. Singh BN, Connolly SJ, Crijns HJ et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007; 357:987-99. [PubMed 17804843]

4. Køber L, Torp-Pedersen C, McMurray JJ et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008; 358:2678-87. [PubMed 18565860]

5. Hoy SM, Keam SJ. Dronedarone. Drugs. 2009; 69:1647-63. [PubMed 19678715]

6. Riera AR, Uchida AH, Ferreira C et al. Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome. Cardiol J. 2008; 15:209-19. [PubMed 18651412]

7. Coletta AP, Cleland JG, Cullington D et al. Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452. Eur J Heart Fail. 2008; 10:917-20. [PubMed 18678526]

8. Garcia D, Cheng-Lai A. Dronedarone: a new antiarrhythmic agent for the treatment of atrial fibrillation. Cardiol Rev. 2009 Sep-Oct; 17:230-4.

9. Sanofi-Aventis, Bridgewater, NJ: Personal communication.

10. Sanofi-Aventis. Healthcare professional information sheet for Multaq (dronedarone). 2009 Jul. Available from website. Accessed 2010 Mar 11.

11. Sanofi-Aventis. Prescribing Multaq: Information for health care professionals. 2009 Dec. Available from website. Accessed 2010 Mar 18.

12. Sanofi-Aventis. Risk evaluation and mitigation strategy (REMS): NDA 22-425 Multaq (dronedarone). 2009 Jun 9. Available from website. Accessed 2010 Mar 18.

13. Tschuppert Y, Buclin T, Rothuizen LE et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007; 64:785-91. [PubMed 17662087]

14. Le Heuzey JY, De Ferrari GM, Radzik D et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation. The DIONYSOS study. J Cardiovasc Electrophysiol. 2010 Jun; 21:597-605. [PubMed 20384650]

15. Savelieva I, Camm J. Update on atrial fibrillation: part II. Clin Cardiol. 2008; 31:102-8. [PubMed 18383050]

16. Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey. N Engl J Med. 2009 Apr; 360:1811-3. Commentary. [PubMed 19403901]

17. Schafer JA, Kjesbo NK, Gleason PP. Dronedarone: current evidence and future questions. Cardiovasc Ther. 2010; 28:38-47. [PubMed 20074258]

18. Singh D, Cingolani E, Diamond GA et al. Dronedarone for atrial fibrillation. Have we expanded the therapeutic armamentarium? JACC. 2010; 55:1569-76. Commentary. [PubMed 20378073]

19. Ezekowitz MD. Maintaining sinus rhythm—making treatment better than the disease. N Engl J Med. 2009; 357:1039-41. Editorial. [PubMed 17804851]

20. Wyse DG, Waldo AL, DiMarco JP et al, for theAtrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347:1825-33. [PubMed 12466506]

21. Falk RH. Management of atrial fibrillation—ra

Monday, March 12, 2012

Simethicone

Class: Antiflatulents
VA Class: GA900
CAS Number: 8050-81-5
Brands: Alka-Seltzer Gas Relief, Flatulex, GasAid, Gas-X, Genasyme, Imodium Advanced, Maalox Anti-Gas, Mylanta Gas Relief, Mylicon, Phazyme

Introduction

Antiflatulent; antifoaming agent.^a

Uses for Simethicone

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pains

Adjunct for symptomatic treatment of flatulence, functional gastric bloating, and postoperative gas pain.^a

Self-medication as an antiflatulent to relieve symptoms of gas (e.g., upper GI bloating, pressure, fullness, stuffed feeling).¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁵

Has been used prior to gastroscopy to enhance visualization and prior to radiography of the intestine to reduce gas shadows.^a

Infant Colic

Not recommended for treatment of infant colic.^a (See Pediatric Use under Cautions.)

Immediate Postprandial Upper Abdominal Distress

Efficacy not established for the symptomatic relief of immediate postprandial upper abdominal distress (IPPUAD);¹⁰¹ ¹⁰² no conclusive evidence that excessive gas causes IPPUAD.¹⁰⁰ ¹⁰¹

Intestinal Distress

Efficacy not established for symptomatic relief of intestinal distress; ¹⁰⁰ ¹⁰¹ no conclusive evidence that gas causes intestinal distress symptoms.¹⁰⁰ ¹⁰¹

Simethicone Dosage and Administration

Administration

Oral Administration

Administer orally after meals and at bedtime, usually in up to 4 divided doses daily; infant drops (oral suspension) can be administered in up to 12 doses daily.^a ^b

Chewable Tablets

Chew thoroughly before swallowing.^a

Oral Suspension

Generally used in infants.^b Shake drops well before use; use dosing device provided by manufacturer for measurement of the dose.^b

Dose may be mixed with 1 ounce cool water, infant formula, or other suitable liquids prior to administration.^b

Orally Dissolving Strips

Place strips on tongue to dissolve.^g

Dosage

Pediatric Patients

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Usual dosage in children >12 years of age: 40–125 mg 4 times daily as needed after meals and at bedtime.^a

Self-medication in children <2 years of age (<10.9 kg): 20 mg (0.3 mL) as needed after meals and at bedtime as oral drops; do not exceed 12 doses (i.e., 240 mg) daily.^b

Self-medication in children 2–12 years of age (>10.9 kg): 40 mg as needed after meals and at bedtime; do not exceed 12 doses (i.e., 480 mg) daily.^b

Self-medication in children >12 years of age: 40–125 mg as needed after meals and at bedtime; do not exceed 500 mg daily.^a

Adults

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Usual dosage: 40–125 mg 4 times daily as needed after meals and at bedtime.^a

Self-medication: 40^a –250^c mg as needed after meals and at bedtime; do not exceed 500 mg daily.^a ¹⁰⁵

Diagnostic Aid Prior to Gastroscopy or Radiography of the Intestine

Oral

67 mg as a single dose of oral suspension, in 2.5 mL of water.^a

Prescribing Limits

Pediatric Patients

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Self-medication in children <2 years of age (weight <10.9 kg): Maximum 12 doses (i.e., 240 mg) daily.^b

Self-medication in children 2–12 years of age (weight >10.9 kg): Maximum 12 doses (i.e., 480 mg) daily.^b

Self-medication in children >12 years of age: Maximum 500 mg daily.^a

Adults

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Self-medication: Maximum 500 mg daily.^a ¹⁰⁵

Special Populations

No special population dosage recommendations at this time.^a

Cautions for Simethicone

Warnings/Precautions

General Precautions

Simethicone is apparently nontoxic; no adverse effects reported.^a

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category C.^d

Lactation

Distribution into milk not expected; simethicone not orally absorbed.^d

Pediatric Use

Safety information in infants and children limited; not recommended for treatment of infant colic.^a

Simethicone Pharmacokinetics

Absorption

Bioavailability

Not absorbed following oral administration.^a

Food

Does not interfere with the absorption of nutrients or with gastric secretion.^a

Elimination

Elimination Route

Excreted unchanged in feces.^a

Stability

Storage

Oral

Capsules, Liquid-filled

20–25°C; avoid temperatures >40°C.^e ^f Protect from moisture.^f

Strips, Orally Dissolving

20–25°C.^g Protect from moisture.^g

Tablets and Chewable Tablets

Tight, well-closed containers at <40°C; preferably 15–30°C.^a Avoid high humidity.^c

Suspension

Tight, light resistant containers at <40°C; preferably 15–30°C.^a Avoid freezing.^a ^b

ActionsActions

Silicone antifoams spread on the surface of aqueous liquids, forming a low surface tension film and causing collapse of foam bubbles.^a

May allow mucus-surrounded gas bubbles in the GI tract to coalesce and be expelled.^a

Advice to Patients

Importance of not exceeding recommended self-medication dosage, unless otherwise instructed by a clinician.^b

Advise patients to dispense recommended dose of infant drops (oral suspension) slowly into the infant's mouth with enclosed dropper, toward the inner cheek.^b

Advise patients that oral suspension may be mixed with 1 ounce cool water, infant formula, or other suitable liquids.^b

Importance of not chewing liquid-filled capsules.^a

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Simethicone
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	125 mg	Alka-Seltzer Gas Relief Maximum Strength Softgels	Bayer
			GasAid Maximum Strength Softgels	McNeil
			Gas-X Extra Strength Softgels	Novartis
			Mylanta Gas Maximum Strength Softgels	J&J-Merck
		180 mg	Phazyme-Ultra Strength Gas Relief Softgels	GlaxoSmithKline
	Strips, orally dissolving	62.5 mg	Gas-X Thin Strips	Novartis
	Suspension	40 mg/0.6 mL*	Baby Gas-X Infant Drops	Novartis
			Flatulex Drops	Dayton
			Genasyme Drops	Teva
			Mylicon Infant’s Drops	J&J-Merck
	Tablets, chewable	80 mg*	Gas-X (scored)	Novartis
			Genasyme	Teva
			Maalox Anti-Gas Regular Strength	Novartis
		125 mg	Gas-X Extra Strength (scored)	Novartis
			Mylanta Gas Relief Maximum Strength (scored)	J&J-Merck
			Simethicone Tablets	Rugby
		150 mg	Maalox Anti-Gas Extra Strength	Novartis

Simethicone is also commercially available in combination with antacids, antispasmodics, and digestants.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Simethicone Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	125 mg with Loperamide Hydrochloride 2 mg	Imodium Advanced Caplets	McNeil
	Tablets, chewable	125 mg with Loperamide Hydrochloride 2 mg*	Imodium Advanced Chewable Tablets	McNeil

Disclaimer

References

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. Digestive aid products for over-the-counter human use; establishment of a monograph. [21 CFR Part 357; Docket No. 81N-0106] Fed Regist. 1982; 47:454-87.

101. Food and Drug Administration. Digestive aid products for over-the-counter human use; tentative final monograph. [21 CFR Part 357; Docket No. 81N-0106] Fed Regist. 1988; 53:2706-14. (IDIS 240339)

102. Food and Drug Administration. Antiflatulent drug products for over-the-counter human use; proposed amendment of monograph. [21 CFR Part 332; Docket No. 87N-0053] Fed Regist. 1988; 53:2716-7. (IDIS 240340)

103. Food and Drug Administration. Over-the-counter drugs: proposal establishing a monograph for antacid products. [21 CFR Part 130] Fed Regist. 1973; 38:8714-24.

104. Food and Drug Administration. Over-the-counter drugs generally recognized as safe and effective and not misbranded: tentative final order for antacid products. [21 CFR Part 130] Fed Regist. 1973; 38:31258-69.

105. Food and Drug Administration. Antacid products for over-the-counter (OTC) human use. Antiflatulent products for over-the-counter (OTC) human use. Final order for antacid and antiflatulent products generally recognized as safe and effective and not misbranded. [21 CFR Parts 331 and 332] Fed Regist. 1974; 39:19862-77.

a. AHFS drug information 2007. McEvoy GK, ed. Simethicone. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2918-9.

b. Johnson & Johnson. Infants' Mylicon Drops (simethicone) product information. 2006 June. From Mylicon webiste.

c. Johnson & Johnson. Mylanta Gas Maximum Strength Chewable Tablets (simethicone) product information. 2006 June. From Mylanta website.

d. Simethicone. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1469.

e. Bayer Consumer Care. Alka-Seltzer Gas Relief (simethicone) Liquid Softgels product information. Undated. From product website. Accessed 2007 Jul 12.

f. Novartis Consumer Health. Gas-X (simethicone) Maximum Strength Softgels product information. Undated. From product website. Accessed 2007 Jul 12.

g. Novartis Consumer Health. Gas-X (simethicone) Thin Strips product information. Undated. From product website. Accessed 2007 Jul 12.

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Genasyme Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

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