Boots Alternatives Calendula Sore Skin Relief

1. Name Of The Medicinal Product

Calendula Cream

Boots Alternatives Calendula Sore Skin Relief

2. Qualitative And Quantitative Composition

Calendula officinalis tincture 1/10

HSE 9.0% v/w

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

A topical herbal remedy traditionally used for the symptomatic relief of sore and rough skin.

4.2 Posology And Method Of Administration

By external application. Apply a little cream and rub away lightly.

The dosage is the same for adults, children and the elderly.

4.3 Contraindications

Known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

None.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not known.

4.6 Pregnancy And Lactation

As with many other medicaments, use during this period is at the physician's discretion.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Not known.

4.9 Overdose

Not known

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Not applicable.

Used in accordance with homoeopathic tradition by reference to homoeopathic materia medica.

5.2 Pharmacokinetic Properties

Not applicable.

Used in accordance with homoeopathic tradition by reference to homoeopathic materia medica.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Purified Water

White soft paraffin

Cetearyl Alchol, PEG-20 Stearate

Methyl parahydroxybenzoate

Fragrance

Honey

Propyl parahydroxybenzoate

6.2 Incompatibilities

Not known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Epoxy phenolic lacquered aluminium tube. Polyethylene cap. 30 g.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

Administrative Data

7. Marketing Authorisation Holder

A. Nelson & Co. Ltd.

5 Endeavour Way

Wimbledon

London

SW19 9UH

Trading style: Nelsons Homoeopathy

8. Marketing Authorisation Number(S)

PL 01175/5040R

9. Date Of First Authorisation/Renewal Of The Authorisation

Renewal of authorisation: 29/05/96

10. Date Of Revision Of The Text

03/09/2003

Clomid

Generic Name: clomiphene citrate

Dosage Form: tablets

Clomid Description

Clomid (clomiphene citrate tablets USP) is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy] triethylamine citrate (1:1). It has the molecular formula of C26H28ClNO • C6H8O7 and a molecular weight of 598.09. It is represented structurally as:

Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline powder. It is freely soluble in methanol; soluble in ethanol; slightly soluble in acetone, water, and chloroform; and insoluble in ether.

Clomid is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer.

Each white scored tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized cornstarch, and sucrose.

Clomid - Clinical Pharmacology

Action

Clomid is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, Clomid has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy.

Clomiphene citrate is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomiphene citrate initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomiphene therapy is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis, resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.

Available data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation. The two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. Some data suggest that zuclomiphene has greater estrogenic activity than enclomiphene.

Clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

Although there is no evidence of a "carryover effect" of Clomid, spontaneous ovulatory menses have been noted in some patients after Clomid therapy.

Pharmacokinetics

Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Cumulative urinary and fecal excretion of the 14C averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.

Some 14C label was still present in the feces 6 weeks after administration. Subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer half-life than enclomiphene (trans). Detectable levels of zuclomiphene persisted for longer than a month in these subjects. This may be suggestive of stereo-specific enterohepatic recycling or sequestering of the zuclomiphene. Thus, it is possible that some active drug may remain in the body during early pregnancy in women who conceive in the menstrual cycle during Clomid therapy.

Clinical Studies

During clinical investigations, 7578 patients received Clomid, some of whom had impediments to ovulation other than ovulatory dysfunction (see INDICATIONS AND USAGE). In those clinical trials, successful therapy characterized by pregnancy occurred in approximately 30% of these patients.

There were a total of 2635 pregnancies reported during the clinical trial period. Of those pregnancies, information on outcome was only available for 2369 of the cases. Table 1 summarizes the outcome of these cases.

Of the reported pregnancies, the incidence of multiple pregnancies was 7.98%: 6.9% twin, 0.5% triplet, 0.3% quadruplet, and 0.1% quintuplet. Of the 165 twin pregnancies for which sufficient information was available, the ratio of monozygotic to dizygotic twins was about 1:5. Table 1 reports the survival rate of the live multiple births.

A sextuplet birth was reported after completion of original clinical studies; none of the sextuplets survived (each weighed less than 400 g), although each appeared grossly normal.

Table 1. Outcome of Reported Pregnancies in Clinical Trials (n = 2369)

Outcome	Total Number of Pregnancies	Survival Rate
* Includes 28 ectopic pregnancies, 4 hydatiform moles, and 1 fetus papyraceous. † Indicates percentage of surviving infants from these pregnancies.
Pregnancy Wastage
Spontaneous Abortions	483*
Stillbirths	24
Live Births
Single Births	1697	98.16%†
Multiple Births	165	83.25%†

The overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%.

Indications and Usage for Clomid

Clomid is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning Clomid therapy. Those patients most likely to achieve success with clomiphene therapy include patients with polycystic ovary syndrome (see WARNINGS: Ovarian Hyperstimulation Syndrome), amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology.

Properly timed coitus in relationship to ovulation is important. A basal body temperature graph or other appropriate tests may help the patient and her physician determine if ovulation occurred. Once ovulation has been established, each course of Clomid should be started on or about the 5th day of the cycle. Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles). (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.)

Clomid is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below (see CONTRAINDICATIONS):

1. Patients who are not pregnant.


2. Patients without ovarian cysts. Clomid should not be used in patients with ovarian enlargement except those with polycystic ovary syndrome. Pelvic examination is necessary prior to the first and each subsequent course of Clomid treatment.


3. Patients without abnormal vaginal bleeding. If abnormal vaginal bleeding is present, the patient should be carefully evaluated to ensure that neoplastic lesions are not present.


4. Patients with normal liver function.

In addition, patients selected for Clomid therapy should be evaluated in regard to the following:

1. Estrogen Levels. Patients should have adequate levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen, or from bleeding in response to progesterone). Reduced estrogen levels, while less favorable, do not preclude successful therapy.


2. Primary Pituitary or Ovarian Failure. Clomid therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure.


3. Endometriosis and Endometrial Carcinoma. The incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. Endometrial biopsy should always be performed prior to Clomid therapy in this population.


4. Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility.


5. Uterine Fibroids. Caution should be exercised when using Clomid in patients with uterine fibroids due to the potential for further enlargement of the fibroids.

There are no adequate or well-controlled studies that demonstrate the effectiveness of Clomid in the treatment of male infertility. In addition, testicular tumors and gynecomastia have been reported in males using clomiphene. The cause and effect relationship between reports of testicular tumors and the administration of Clomid is not known.

Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (ie, Clomid in conjunction with other ovulation-inducing drugs). Similarly, there is no standard Clomid regimen for ovulation induction in in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, Clomid is not recommended for these uses.

Contraindications

Hypersensitivity

Clomid is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.

Pregnancy

Clomid should not be administered during pregnancy. Clomid may cause fetal harm in animals (see Animal Fetotoxicity). Although no causative evidence of a deleterious effect of Clomid therapy on the human fetus has been established, there have been reports of birth anomalies which, during clinical studies, occurred at an incidence within the range reported for the general population (see Fetal/Neonatal Anomalies and Mortality; ADVERSE REACTIONS).

To avoid inadvertent Clomid administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation occurs. The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. The next course of Clomid therapy should be delayed until these conditions have been excluded.

Fetal/Neonatal Anomalies and Mortality

The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with Clomid during clinical trials. Each of the following fetal abnormalities were reported at a rate of <1% (experiences are listed in order of decreasing frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. Neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of <1%. The overall incidence of reported birth anomalies from pregnancies associated with maternal Clomid ingestion during clinical studies was within the range of that reported for the general population.

In addition, reports of birth anomalies have been received during postmarketing surveillance of Clomid (see ADVERSE REACTIONS).

Animal Fetotoxicity

Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate.

Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormal reproductive behavior and sterility described with other estrogens and antiestrogens.

In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring.

Liver Disease

Clomid therapy is contraindicated in patients with liver disease or a history of liver dysfunction (see also INDICATIONS AND USAGE and ADVERSE REACTIONS).

Abnormal Uterine Bleeding

Clomid is contraindicated in patients with abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE).

Ovarian Cysts

Clomid is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE and WARNINGS).

Other

Clomid is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor (see INDICATIONS AND USAGE).

Warnings

Visual Symptoms

Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with Clomid. These visual symptoms increase in incidence with increasing total dose or therapy duration and generally disappear within a few days or weeks after Clomid is discontinued. Patients should be warned that these visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.

These visual symptoms appear to be due to intensification and prolongation of afterimages. Symptoms often first appear or are accentuated with exposure to a brightly lit environment. While measured visual acuity usually has not been affected, a study patient taking 200 mg Clomid daily developed visual blurring on the 7th day of treatment, which progressed to severe diminution of visual acuity by the 10th day. No other abnormality was found, and the visual acuity returned to normal on the 3rd day after treatment was stopped.

Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported. A patient treated during clinical studies developed phosphenes and scotomata during prolonged Clomid administration, which disappeared by the 32nd day after stopping therapy.

Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during Clomid therapy (see ADVERSE REACTIONS).

While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly.

Ovarian Hyperstimulation Syndrome

The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving clomiphene citrate therapy for ovulation induction. In some cases, OHSS occurred following cyclic use of clomiphene citrate therapy or when clomiphene citrate was used in combination with gonadotropins. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with ovarian hyperstimulation syndrome (OHSS).

OHSS is a medical event distinct from uncomplicated ovarian enlargement. The clinical signs of this syndrome in severe cases can include gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. In addition, the following symptoms have been reported in association with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress. The early warning signs of OHSS are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels, varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If conception results, rapid progression to the severe form of the syndrome may occur.

To minimize the hazard associated with occasional abnormal ovarian enlargement associated with Clomid therapy, the lowest dose consistent with expected clinical results should be used. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the recommended dose of Clomid. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of Clomid. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy (see DOSAGE AND ADMINISTRATION).

If enlargement of the ovary occurs, additional Clomid therapy should not be given until the ovaries have returned to pretreatment size, and the dosage or duration of the next course should be reduced. Ovarian enlargement and cyst formation associated with Clomid therapy usually regresses spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent Clomid therapy in these cases should exceed the risk. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.

A causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. However, because a correlation between ovarian cancer and nulliparity, infertility, and age has been suggested, if ovarian cysts do not regress spontaneously, a thorough evaluation should be performed to rule out the presence of ovarian neoplasia.

Precautions

General

Careful attention should be given to the selection of candidates for Clomid therapy. Pelvic examination is necessary prior to Clomid treatment and before each subsequent course (see CONTRAINDICATIONS and WARNINGS).

Information for Patients

The purpose and risks of Clomid therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of Clomid therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks:

Visual Symptoms

Advise that blurring or other visual symptoms occasionally may occur during or shortly after Clomid therapy. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting (see WARNINGS).

The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed.

Abdominal/Pelvic Pain or Distention

Ovarian enlargement may occur during or shortly after therapy with Clomid. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort, or distention after taking Clomid (see WARNINGS).

Multiple Pregnancy

Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to Clomid therapy. The potential complications and hazards of multiple pregnancy should be explained.

Pregnancy Wastage and Birth Anomalies

The physician should explain the assumed risk of any pregnancy, whether ovulation is induced with the aid of Clomid or occurs naturally. The patient should be informed of the greater risks associated with certain characteristics or conditions of any pregnant woman, eg, age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history, organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, that may be pertinent to the patient for whom Clomid is being considered. Based upon the evaluation of the patient, genetic counseling may be indicated.

The overall incidence of reported birth anomalies from pregnancies associated with maternal Clomid ingestion during the investigational studies was within the range of that reported in published references for the general population. (See CONTRAINDICATIONS: Pregnancy.)

During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%. (See CLINICAL PHARMACOLOGY.)

Drug Interactions

Drug interactions with Clomid have not been documented.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiphene citrate.

Oral administration of Clomid to male rats at doses of 0.3 or 1 mg/kg/day caused decreased fertility, while higher doses caused temporary infertility. Oral doses of 0.1 mg/kg/day in female rats temporarily interrupted the normal cyclic vaginal smear pattern and prevented conception. Doses of 0.3 mg/kg/day slightly reduced the number of ovulated ova and corpora lutea, while 3 mg/kg/day inhibited ovulation.

Pregnancy

Pregnancy Category X. (See CONTRAINDICATIONS.)

Nursing Mothers

It is not known whether Clomid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Clomid is administered to a nursing woman. In some patients, Clomid may reduce lactation.

Ovarian Cancer

Prolonged use of clomiphene citrate tablets USP may increase the risk of a borderline or invasive ovarian tumor (see ADVERSE REACTIONS).

Adverse Reactions

Clinical Trial Adverse Events

Clomid, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiphene citrate during clinical studies are shown in Table 2.

Table 2. Incidence of Adverse Events in Clinical Studies (Events Greater than 1%) (n = 8029*)

Adverse Event	%
* Includes 498 patients whose reports may have been duplicated in the event totals and could not be distinguished as such. Also, excludes 47 patients who did not report symptom data.
Ovarian Enlargement	13.6
Vasomotor Flushes	10.4
Abdominal-Pelvic Discomfort/Distention/Bloating	5.5
Nausea and Vomiting	2.2
Breast Discomfort	2.1
Visual Symptoms	1.5
Blurred vision, lights, floaters, waves, unspecified visual complaints, photophobia, diplopia, scotomata, phosphenes
Headache	1.3
Abnormal Uterine Bleeding	1.3
Intermenstrual spotting, menorrhagia

The following adverse events have been reported in fewer than 1% of patients in clinical trials: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss.

Patients on prolonged Clomid therapy may show elevated serum levels of desmosterol. This is most likely due to a direct interference with cholesterol synthesis. However, the serum sterols in patients receiving the recommended dose of Clomid are not significantly altered. Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

Postmarketing Adverse Events

The following adverse experiences were reported spontaneously with Clomid. The cause and effect relationship of the listed events to the administration of Clomid is not known.

Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus

Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope

Psychiatric: Anxiety, irritability, mood changes, psychosis

Visual Disorders: Abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary loss of vision

Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis

Musculoskeletal: Arthralgia, back pain, myalgia

Hepatic: Transaminases increased, hepatitis

Neoplasms: Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abcess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, Hodgkin's lymphoma, tongue carcinoma, bladder carcinoma); and neoplasms of offspring (neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia)

Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage

Body as a Whole: Fever, tinnitus, weakness

Other: Leukocytosis, thyroid disorder

Fetal/Neonatal Anomalies

The following fetal abnormalities have also been reported during postmarketing surveillance: delayed development; abnormal bone development including skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot, and joints; tissue malformations including imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, renal agenesis and dysgenesis, and malformations of the eye and lens (cataract), ear, lung, heart (ventricular septal defect and tetralogy of Fallot), and genitalia; as well as dwarfism, deafness, mental retardation, chromosomal disorders, and neural tube defects (including anencephaly).

Drug Abuse and Dependence

Tolerance, abuse, or dependence with Clomid has not been reported.

Overdosage

Signs and Symptoms

Toxic effects accompanying acute overdosage of Clomid have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during Clomid therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain. (See CONTRAINDICATIONS: Ovarian Cyst.)

Oral LD50

The acute oral LD50 of Clomid is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.

Dialysis

It is not known if Clomid is dialyzable.

Treatment

In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.

Clomid Dosage and Administration

General Considerations

The workup and treatment of candidates for Clomid therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with Clomid only after careful diagnostic evaluation (see INDICATIONS AND USAGE). The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning Clomid. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy.

Ovulation most often occurs from 5 to 10 days after a course of Clomid. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.

Recommended Dosage

Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg Clomid. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome (see WARNINGS; Ovarian Hyperstimulation Syndrome).

The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.

If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.

If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended.

The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with Clomid is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about six cycles (see PRECAUTIONS).

How is Clomid Supplied

NDC 0068-0226-30: 50 mg tablets in cartons of 30

Tablets are round, white, scored, and debossed Clomid 50.

Store tablets at controlled room temperature 59–86°F (15–30°C). Protect from heat, light, and excessive humidity, and store in closed containers.

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

June 2006

©2006 sanofi-aventis U.S. LLC

Clomid  clomiphene citrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0068-0226 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength clomiphene citrate (clomiphene) Active 50 MILLIGRAM  In 1 TABLET corn starch Inactive   lactose Inactive   magnesium stearate Inactive   pregelatinized cornstarch Inactive   sucrose Inactive

Product Characteristics Color white (WHITE) Score 2 pieces Shape ROUND (ROUND) Size 9mm Flavor Imprint Code Clomid;50 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0068-0226-30 30 TABLET In 1 CARTON None

Revised: 03/2009sanofi-aventis U.S. LLC

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Compare Clomid with other medications

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ACWY Vax Vaccine

1. Name Of The Medicinal Product

ACWY Vax - powder and solvent for solution for injection in a pre-filled syringe

Meningococcal polysaccharide groups A, C, Y and W₁₃₅ vaccine

2. Qualitative And Quantitative Composition

After reconstitution, 1 dose (0.5 ml) contains:
Neisseria meningitidis group A polysaccharide	50 µg
Neisseria meningitidis group C polysaccharide	50 µg
Neisseria meningitidis group Y polysaccharide	50 µg
Neisseria meningitidis group W135 polysaccharide	50 µg
For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection in a pre-filled syringe.

The powder is white. The solvent is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

Active immunisation of children older than 2 years, adolescents and adults against invasive meningococcal disease caused by meningococci of groups A, C, W₁₃₅ and Y.

ACWY Vax should be used in accordance with available official recommendations.

4.2 Posology And Method Of Administration

Posology

One dose of 0.5 ml.

Subjects who remain at increased risk of invasive meningococcal disease may be revaccinated at intervals (see persistence of immune response in Section 5.1). Intervals should be in accordance with available official recommendations.

Method of administration

ACWY Vax is for deep subcutaneous injection only.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Hypersensitivity after previous administration of ACWY Vax.

As with other vaccines, the administration of ACWY Vax should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection, such as a cold, is not a contra-indication for immunisation.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of anaphylactic reactions following the administration of the vaccine.

Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.

ACWY Vax should under no circumstances be administered intravascularly or intradermally.

ACWY Vax will only confer protection against Neisseria meningitidis groups A, C, W₁₃₅ and Y. Protection cannot be guaranteed in every individual vaccinated.

The vaccine may not elicit a protective immune response in subjects with impaired immune systems.

Group C, W₁₃₅ and Y polysaccharides are poorly immunogenic in children less than 24 months of age. Group A polysaccharide induces an antibody response in children from the age of 6 months. However, the response is lower than that observed in older subjects and may be transient.

Group C polysaccharide may induce immunological hyporesponsiveness to further doses of polysaccharide C or to meningococcal group C conjugate vaccine. The clinical relevance of this phenomenon remains unknown.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no data on concomitant administration of ACWY Vax and other vaccines.

Different injection sites should be used when concomitant administration with other injectable vaccines can not be avoided.

4.6 Pregnancy And Lactation

Pregnancy

Adequate human data on use during pregnancy and adequate animal reproduction studies are not available.

Nevertheless, vaccination during pregnancy may be considered when there is an increased risk for meningococcal disease.

Lactation

Adequate data on the administration of ACWY Vax to women who are breast-feeding are not available.

However, ACWY Vax may be administered to breast-feeding women when there is an increased risk of meningococcal disease.

4.7 Effects On Ability To Drive And Use Machines

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

4.8 Undesirable Effects

In recent clinical studies, ACWY Vax was administered to 502 subjects.

The most commonly reported adverse reactions were pain at the injection site and redness at the injection site.

Adverse reactions occurring during these studies were mostly reported within 48 hours following vaccination.

Adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency as follows.

Frequencies are reported as:

Very common: (

Common: (

Uncommon: (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders:

Very Common: headache

Common: drowsiness

Uncommon: dizziness

Gastrointestinal disorders:

Common: gastrointestinal symptoms e.g. nausea, vomiting and diarrhoea

Skin and subcutaneous tissue disorders:

Uncommon: urticaria, rash

Metabolism and nutrition disorders:

Common: loss of appetite

General disorders and administration site conditions:

Very common: pain, redness at the injection site, fatigue

Common: fever, swelling at the injection site

Psychiatric disorders:

Common: irritability

In a WHO study conducted in Ghana, ACWY Vax was administered to 177 adults. The following adverse reactions were observed in this trial:

Very common: tenderness at injection site

Common: induration at injection site.

In addition, the following adverse reactions have been reported during post-marketing surveillance:

Skin and subcutaneous tissue disorders:

Angioneurotic oedema

Musculoskeletal and connective tissue disorders:

Arthralgia, musculoskeletal stiffness

General disorders and administration site conditions:

Influenza-like symptoms, chills

Immune system disorders:

Allergic reactions, including anaphylactic and anaphylactoid reactions

4.9 Overdose

Cases of overdose (up to 10 times the recommended dose) have been reported during post-marketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Bacterial vaccines, ATC code: J07AH04

Immunogenicity data

ACWY Vax induces bactericidal antibodies against meningococci of groups A, C, W₁₃₅ and Y.

The current formulation of ACWY Vax was shown immunologically non-inferior to the previous formulation of the vaccine in a trial conducted in Lebanon in 161 subjects aged 2-30 years.

The immunogenicity of the previous formulation of ACWY Vax was evaluated in four clinical studies conducted in Belgium, Lebanon, Poland and Taiwan (N =341) in subjects aged 2-30 years.

Antibody titres were measured with the serum bactericidal assay (SBA).

Vaccine response was defined as seroconversion for initially seronegative subjects (with SBA titre below 1:8) or as four-fold increase in SBA titre from pre to post vaccination for initially seropositive subjects.

The percentage of vaccine responders observed in the four clinical studies conducted with the previous formulation were as follows:

In children aged 2-5 years: Group A - 69.1%, Group C - 93.1%, Group W₁₃₅ - 89.3%, Group Y - 79.2%.

In subjects aged 6-30 years: Group A - 72.2%, Group C - 95.4%, Group W₁₃₅ - 92.3%, Group Y -81.2%.

In initially seronegative subjects seroconversion rates were 100% for Group A and Y, and at least 92.9% for Group C and W_135.

The risk of meningococcal disease is much higher in individuals with late complement component deficiency (LCCD) because of their inability to kill meningococci via the classical and alternative pathways. However, ACWY Vax induces anti-capsular polysaccharide antibodies against each of the four groups in LCCD subjects. In spite of the complement deficiency, killing of meningococci A, C, W₁₃₅ and Y is observed when sera from LCCD subjects vaccinated with ACWY Vax are incubated with human neutrophils.

Efficacy data

In response to a meningococcal disease epidemic in Burkina Faso, a mass vaccination campaign with Mencevax ACW was performed in more than 1.68 million children and adults aged from 2 to 29 years. The vaccine effectiveness against group A and W₁₃₅ disease was 95.8% (95% CI: 81.8%-99.0%) for persons with reported vaccination.

Persistence of immune response

Literature data supports the persistence of vaccine induced antibody response for at least 3 years.

An ongoing clinical study has demonstrated that 100% of subjects aged 18-25 years had bactericidal antibody titres ₁₃₅ and Y and 96% for group C two years after vaccination.

In a study conducted in Ghana in 177 subjects aged 15-34 years, 100%, 88.4% and 93.5% of subjects had SBA titres ₁₃₅, respectively at approximately one year after vaccination with ACWY Vax.

In studies conducted among complement-deficient subjects, the antibodies persisted for 3 years post vaccination with ACWY Vax and the revaccination restored antibody concentrations.

5.2 Pharmacokinetic Properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on general safety tests performed in animals.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder :

Sucrose

Trometamol

Solvent:

Sodium chloride

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

3 years.

After reconstitution, the vaccine should be used immediately. However, chemical and physical in-use stability has been demonstrated for 8 hours at 2-8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Powder in a vial (type I glass) with a stopper and solvent (0.5 ml) in a pre-filled syringe (type I glass) with a stopper with or without needles– pack size of 1.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The vaccine should be inspected visually for any foreign particulate matter and/or other coloration prior to administration. In the event of either being observed, discard the vaccine.

ACWY Vax must be reconstituted by adding the entire content of the supplied container of solvent to the vial containing the powder. The powder should be completely dissolved in the solvent.

The reconstituted vaccine is a clear colourless solution.

7. Marketing Authorisation Holder

SmithKline Beecham plc

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 10592/0301

9. Date Of First Authorisation/Renewal Of The Authorisation

23/06/2008

10. Date Of Revision Of The Text

09/02/2011

POM

Liver and Pancreatic Disease Medications

Definition of Liver and Pancreatic Disease: The term "liver disease" can apply to many diseases and disorders that cause the liver to function improperly or cease functioning. Abnormal results of liver function tests often suggest liver disease.

Topics under Liver and Pancreatic Disease

• Benign Liver Tumor (0 drugs)

• Hepatic Coma (13 drugs in 2 topics)

• Hepatic Tumor (2 drugs in 2 topics)

• Hyperbilirubinemia (2 drugs)

• Liver Abscess (0 drugs)

• Liver Cirrhosis (4 drugs in 3 topics)

• Liver Metastasis in Adenocarcinoma (1 drug)

• Nonalcoholic Fatty Liver Disease (7 drugs)

• Pancreatic Exocrine Dysfunction (34 drugs)

• Pancreatitis (48 drugs in 2 topics)

Learn more about Liver and Pancreatic Disease

Micromedex Care Notes:

• Fulminant Hepatic Failure
• Jaundice In Newborns
• Liver Abscess
• Non-alcoholic Fatty Liver Disease

Medical Encyclopedia:

• ALT
• Cirrhosis
• Crigler-Najjar syndrome
• Hepatitis B
• Hepatomegaly
• Hypertension
• Jaundice - yellow skin
• Liver disease
• Liver scan
• Newborn jaundice

Drug List:

Multaq 400mg tablets

1. Name Of The Medicinal Product

MULTAQ 400 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each tablet contains 400 mg of dronedarone (as hydrochloride).

Excipients:

Each tablet also contains 41.65 mg of lactose (as monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

White, oblong shaped tablets, engraved with a double wave marking on one side and “4142”code on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

MULTAQ is indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation (AF). Due to its safety profile (see sections 4.3 and 4.4), Multaq should only be prescribed after alternative treatment options have been considered.

MULTAQ should not be given to patients with left ventricular systolic dysfunction or to patients with current or previous episodes of heart failure.

4.2 Posology And Method Of Administration

Treatment should be initiated and monitored only under specialist supervision (see section 4.4).

Treatment with MULTAQ can be initiated in an outpatient setting.

The recommended dose is 400 mg twice daily in adults. It should be taken as

• one tablet with the morning meal and

• one tablet with the evening meal.

Grapefruit juice should not be taken together with MULTAQ (see section 4.5).

If a dose is missed, patients should take the next dose at the regular scheduled time and should not double the dose.

Treatment with Class I or III antiarrhythmics (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting MULTAQ

There is limited information on the optimal timing to switch from amiodarone to MULTAQ. It should be considered that amiodarone may have a long duration of action after discontinuation due to its long half life. If a switch is envisaged, this should be done under the supervision of a specialist (see sections 4.3 and 5.1).

Paediatric Population

The safety and efficacy of MULTAQ in children aged below 18 years of age have not yet been established. No data are available.

Elderly

Efficacy and safety were comparable in elderly patients who did not suffer from other cardiovascular diseases and younger patients. Caution is needed in patients

Hepatic impairment

MULTAQ is contraindicated in patients with severe hepatic impairment because of the absence of data (see section 4.3 and 4.4). No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).

Renal impairment

MULTAQ is contraindicated in patients with severe renal impairment (creatinine clearance (CrCl) <30 ml/min) (see section 4.3). No dose adjustment is required in other patients with renal impairment (see sections 4.4 and 5.2).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients

• Second- or third- degree Atrio-Ventricular block, complete bundle branch block, distal block, sinus node dysfunction, atrial conduction defects, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker).

• Bradycardia <50 beats per minute (bpm)

• Permanent AF with an AF duration

• Patients in unstable hemodynamic conditions,

• History of, or current heart failure or left ventricular systolic dysfunction

• Patients with liver and lung toxicity related to the previous use of amiodarone

• Co-administration with potent cytochrome P 450 (CYP) 3A4 inhibitors, such as ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir (see section 4.5)

• Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and certain oral macrolides (such as erythromycin), Class I and III antiarrhythmics (see section 4.5)

• QTc Bazett interval

• Severe hepatic impairment

• Severe renal impairment (CrCl <30ml/min)

4.4 Special Warnings And Precautions For Use

Careful monitoring during dronedarone administration is recommended by regular assessment of cardiac, hepatic and pulmonary function (see below). If AF reoccurs discontinuation of dronedarone should be considered. Treatment with dronedarone should be stopped during the course of treatment, in case the patient develops any of the conditions which would lead to a contraindication as mentioned in section 4.3. Monitoring of co-administered drugs like digoxin and anti-coagulants is necessary.

Patients developing permanent AF during treatment

A clinical study in patients with permanent AF (AF duration for at least 6 months) and cardiovascular risk factors was stopped early due to an excess of cardiovascular death, stroke and heart failure in patients receiving MULTAQ (see section 5.1). It is recommended to perform ECGs serially, at least every 6 months. If patients treated with MULTAQ develop permanent AF, treatment with MULTAQ should be discontinued.

Patients with history of, or current heart failure or left ventricular systolic dysfunction

MULTAQ is contraindicated in patients in unstable hemodynamic conditions, with history of, or current heart failure or left ventricular systolic dysfunction (see section 4.3).

Patients should be carefully evaluated for symptoms of Congestive Heart Failure. There have been spontaneously reported events of new or worsening heart failure during treatment with MULTAQ. Patients should be advised to consult a physician if they develop or experience signs or symptoms of heart failure, such as weight gain, dependent oedema, or increased dyspnoea. If heart failure develops, treatment with MULTAQ should be discontinued.

Patients should be followed for the development of left ventricular systolic dysfunction during treatment. If left ventricular systolic dysfunction develops, treatment with MULTAQ should be discontinued.

Patients with coronary artery disease

Caution is needed in patients with coronary artery disease.

Elderly

Caution is needed in elderly patients

Liver Injury

Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients treated with MULTAQ in the post-marketing setting. Liver function tests should be performed prior to initiation of treatment with dronedarone, after one week and after one month following initiation of treatment and then repeated monthly for six months, at months 9 and 12, and periodically thereafter.

If alanine aminotransferase (ALT) levels are elevated

Patients should immediately report any symptoms of potential liver injury (such as sustained new-onset abdominal pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark urine or itching) to their physician.

Management of plasma creatinine increase

An increase in plasma creatinine (mean increase 10 μmol/L) has been observed with dronedarone 400 mg twice daily in healthy subjects and in patients. In most patients this increase occurs early after treatment initiation and reaches a plateau after 7 days. It is recommended to measure plasma creatinine values prior to and 7 days after initiation of dronedarone. If an increase in creatininemia is observed, serum creatinine should be re-measured after a further 7 days. If no further increase in creatinaemia is observed, this value should be used as the new reference baseline taking into account that this may be expected with dronedarone. If serum creatinine continues to rise then consideration should be given to further investigation and discontinuing treatment.

An increase in creatininemia should not necessarily lead to the discontinuation of treatment with ACE inhibitors or Angiotensin II Receptors Antagonists (AIIRAs).

Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen. In most cases, these effects appear to be reversible upon drug discontinuation.

Patients with renal impairment

MULTAQ is contraindicated in patients with CrCl <30 ml/min (see section 4.3).

Electrolytes imbalance

Since antiarrhythmic medicinal products may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before initiation and during dronedarone therapy.

QT prolongation

The pharmacological action of dronedarone may induce a moderate QTc Bazett prolongation (about 10 msec), related to prolonged repolarisation. These changes are linked to the therapeutic effect of dronedarone and do not reflect toxicity. Follow up, including ECG (electrocardiogram), is recommended during treatment. If QTc Bazett interval is

Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease in arrhythmic death in the ATHENA study (see section 5.1).

However, proarrhythmic effects may occur in particular situations such as concomitant use with medicinal products favouring arrhythmia and/or electrolytic disorders (see sections 4.4 and 4.5).

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in post-marketing experience. Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed treatment should be discontinued.

Interactions (see section 4.5)

Digoxin. Administration of dronedarone to patients receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with digoxin toxicity. Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved. A synergistic effect on heart rate and atrioventricular conduction is also possible.

The co-administration of beta-blockers or calcium antagonists with depressant effect on sinus and atrio-ventricular node should be undertaken with caution. These medicinal products should be initiated at low dose and up titration should be done only after ECG assessment. In patients already on calcium antagonists or beta blockers at time of dronedarone initiation, an ECG should be performed and the dose should be adjusted if needed.

Anticoagulation

Patients should be appropriately anti-coagulated as per clinical AF guidelines. International Normalized Ratio (INR) should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per their label.

Dabigatran

Dronedarone increases the exposure of dabigatran (See section 4.5). No clinical data are available regarding the co-administration of these drugs in AF patients. Their co-administration is not recommended.

Potent CYP3A4 inducers such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John's Wort are not recommended.

MAO inhibitors might decrease the clearance of the active metabolite of dronedarone and should therefore be used with caution.

Statins should be used with caution. Lower starting dose and maintenance doses of statins should be considered and patients monitored for clinical signs of muscular toxicity.

Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.

Patients with galactose intolerance

Due to the presence of lactose in this medicinal product, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Dronedarone is primarily metabolised by CYP 3A4 (see section 5.2). Therefore, inhibitors and inducers of CYP 3A4 have the potential to interact on dronedarone.

Dronedarone is a moderate inhibitor of CYP 3A4, a mild inhibitor of CYP 2D6 and a potent inhibitor of P-glycoproteins (P-gp). Dronedarone therefore, has the potential to interact on medicinal products substrates of P-glycoproteins, CYP 3A4 or CYP 2D6. Dronedarone and/or its metabolites also have been shown to inhibit transport proteins of the Organic Anion Transporter (OAT), Organic Anion Transporting Polypeptide (OATP) and Organic Cation Transporter (OCT) families in vitro.

Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6.

A potential pharmacodynamic interaction can also be expected with beta-blockers, calcium antagonists and digitalis.

Medicinal products inducing torsades de pointes

Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides (such as erythromycin), terfenadine and Class I and III antiarrhythmics are contraindicated because of the potential risk of proarrhythmia (see section 4.3). Caution should also be taken with co-administration with beta-blockers or digoxin.

Effect of other medicinal products on MULTAQ

Potent CYP 3A4 inhibitors

Repeated doses of 200 mg ketoconazole daily resulted in a 17-fold increase in dronedarone exposure. Therefore, concomitant use of ketoconazole as well as other potent CYP 3A4 inhibitors such as itraconazole, voriconazole, pozaconazole, ritonavir, telithromycin, clarithromycin or nefazodone is contraindicated (see section 4.3).

Moderate/weak CYP 3A4 inhibitors

Erythromycin

Erythromycin, an oral macrolide, may induce torsades de pointes and, as such, is contraindicated (see section 4.3). Repeated doses of erythromycin (500 mg three times a day for 10 days) resulted in an increase in steady state dronedarone exposure of 3.8 fold.

Calcium antagonists

Calcium antagonists, diltiazem and verapamil, are substrates and/or moderate inhibitors of CYP 3A4. Moreover, due to their heart rate-lowering properties, verapamil and diltiazem have the potential to interact with dronedarone from a pharmacodynamic point of view.

Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine (20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4- and 1.2- fold, respectively. Calcium antagonists also have their exposure increased by dronedarone (400 mg twice daily) (verapamil by 1.4- fold, and nisoldipine by 1.5- fold). In clinical trials, 13% of patients received calcium antagonists concomitantly with dronedarone. There was no increased risk of hypotension, bradycardia and heart failure.

Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium antagonists with depressant effects on sinus and atrio-ventricular node such as verapamil and diltiazem should be used with caution when associated with dronedarone. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already on calcium antagonists at time of dronedarone initiation, an ECG should be performed and the calcium antagonist dose should be adjusted if needed (see section 4.4).

Other moderate/weak CYP 3A4 Inhibitors

Other moderate inhibitors of CYP3A4 are also likely to increase dronedarone exposure.

CYP 3A4 inducers

Rifampicin (600 mg once daily) decreased dronedarone exposure by 80% with no major change on its active metabolite exposure. Therefore, co-administration of rifampicin and other potent CYP 3A4 inducers such as phenobarbital, carbamazepine, phenytoin or St John's Wort is not recommended as they decrease dronedarone exposure.

MAO inhibitors

In an in vitro study MAO contributed to the metabolism of the active metabolite of dronedarone. The clinical relevance of this observation is not known (see sections 4.4 and 5.2).

Effect of MULTAQ on other medicinal products

Interaction on medicinal products metabolized by CYP 3A4

• Statins:

Dronedarone can increase exposure of statins that are substrates of CYP 3A4 and/or P-gp substrates. Dronedarone (400 mg twice daily) increased simvastatin and simvastatin acid exposure by 4- fold and 2- fold respectively. It is predicted that dronedarone could also increase the exposure of lovastatin within the same range as simvastatin acid. There was a weak interaction between dronedarone and atorvastatin (which resulted in a mean 1.7-fold increase in atorvastatin exposure). In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP 3A4.

There was a weak interaction between dronedarone and statins transported by OATP, such as rosuvastatin (which resulted in a mean 1.4-fold increase in rosuvastatin exposure).

As high doses of statins increase the risk of myopathy, concomitant use of statins should be undertaken with caution. Lower starting dose and maintenance doses of statins should be considered according to the statin label recommendations and patients monitored for clinical signs of muscular toxicity (see section 4.4).

• Calcium antagonists

The interaction of dronedarone on calcium antagonists is described above (see section 4.4).

• Sirolimus, tacrolimus

Dronedarone could increase plasma concentrations of tacrolimus and sirolimus. Monitoring of their plasma concentrations and appropriate dose adjustment is recommended in case of coadministration with dronedarone.

• Oral contraceptives

No decreases in ethinylestradiol and levonorgestrel were observed in healthy subjects receiving dronedarone (800 mg twice daily) concomitantly with oral contraceptives.

Interaction on medicinal products metabolized by CYP 2D6: beta blockers, antidepressants

• Beta blockers

Beta blockers that are metabolized by CYP 2D6 can have their exposure increased by dronedarone. Moreover, beta blockers have the potential to interact with dronedarone from a pharmacodynamic point of view. Dronedarone 800 mg daily increased metoprolol exposure by 1.6- fold and propranolol exposure by 1.3-fold (i.e. much below the 6- fold differences observed between poor and extensive CYP 2D6 metabolisers). In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.

Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, beta blockers should be used with caution concomitantly with dronedarone. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already taking beta blockers at time of dronedarone initiation, an ECG should be performed and the beta blocker dose should be adjusted if needed (see section 4.4).

• Antidepressants

Since dronedarone is a weak inhibitor of CYP 2D6 in humans, it is predicted to have limited interaction on antidepressant medicinal products metabolized by CYP 2D6.

Interaction of P-gp substrates

• Digoxin

Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5- fold by inhibiting P-gp transporter. Moreover, digitalis has the potential to interact with dronedarone from a pharmacodynamic point of view. A synergistic effect on heart rate and atrio-ventricular conduction is possible. In clinical trials, increased levels of digitalis and/or gastrointestinal disorders indicating digitalis toxicity were observed when dronedarone was co-administered with digitalis.

The digoxin dose should be reduced by approximately 50%, serum levels of digoxin should be closely monitored and clinical and ECG monitoring is recommended.

• Dabigatran

When dabigatran etexilate 150 mg once daily was co-administered with dronedarone 400 mg twice daily, the dabigatran AUC0-24, and Cmax were increased by 100% and 70%, respectively. No clinical data are available regarding the co-administration of these drugs in AF patients. Their co-administration is not recommended (see section 4.4).

Interaction on warfarin and losartan (CYP 2C9 substrates)

• Warfarin and other vitamin K antagonists

Dronedarone (600 mg twice daily) increased by 1.2- fold S-warfarin with no change in R warfarin and only a 1.07 increase in International Normalized Ratio (INR).

However, clinically significant INR elevations (

• Losartan and other AIIRAs (Angiotensin II Receptor Antagonists)

No interaction was observed between dronedarone and losartan and an interaction between dronedarone and other AIIRAs is not expected.

Interaction on theophylline (CYP 1A2 substrate)

Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure.

Interaction on metformin (OCT1 and OCT2 substrate)

No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate.

Interaction on omeprazole (CYP 2C19 substrate)

Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP 2C19 substrate.

Interaction with clopidogrel

Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.

Other information

Pantoprazole (40 mg once daily), a medicinal product which increases gastric pH without any effect on cytochrome P450, did not interact significantly on dronedarone pharmacokinetics.

Grapefruit juice (CYP 3A4 inhibitor)

Repeated doses of 300 ml of grapefruit juice three times daily resulted in a 3- fold increase in dronedarone exposure. Therefore, patients should be warned to avoid grapefruit juice beverages while taking dronedarone (see section 4.4).

4.6 Pregnancy And Lactation

Fertility

Dronedarone was not shown to alter fertility in animal studies.

Pregnancy

There are no or limited amount of data from the use of dronedarone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). MULTAQ is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether dronedarone and its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dronedarone and its metabolites in milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from MULTAQ therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

a. Summary of the safety profile

The safety profile of dronedarone 400 mg twice daily in patients with atrial fibrillation (AF) or atrial flutter (AFL) is based on 5 placebo controlled studies, in which a total of 6,285 patients were randomised (3,282 patients received dronedarone 400 mg twice daily, and 2,875 received placebo).

The mean exposure across studies was 13 months. In ATHENA study, the maximum follow-up was 30 months.

Assessment of intrinsic factors such as gender or age on the incidence of any treatment emergent adverse reactions showed an interaction for gender (female patients) for the incidence of any adverse reactions and for serious adverse reactions.

In clinical trials, premature discontinuation due to adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2% of patients versus 1.8% in the placebo group).

The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhoea, nausea and vomiting, fatigue and asthenia.

b. Tabulated list of adverse reactions

Table 1 displays adverse reactions associated with dronedarone 400 mg twice daily in AF or AFL patients, presented by system organ class and by decreasing order of frequency.

Frequencies are defined as: very common (

Table 1: Adverse Reactions

System organ class	Very Common (	Common (	Uncommon (	Rare (
Nervous system disorders			Dysgeusia	Ageusia
Cardiac disorders	Congestive heart failure (see sub section c)	Bradycardia
Respiratory, thoracic and mediastinal disorders			Interstitial lung disease including pneumonitis and pulmonary fibrosis (see sub section c)
Gastrointestinal disorders		Diarrhoea Vomiting Nausea Abdominal pains Dyspepsia
Hepatobiliary disorders		Liver function test abnormalities		Hepatocellular liver injury, including life-threatening acute liver failure (see section 4.4)
Skin and subcutaneous tissue disorders		Rashes (including generalised, macular, maculo-papular) Pruritus	Erythemas (including erythema and rash erythematous) Eczema Photosensitivity reaction Dermatitis allergic Dermatitis
General disorders and administration site conditions		Fatigue Asthenia
Investigations	Blood creatinine increased* QTc Bazett prolonged #

*

# >450 msec in male >470 msec in female

c. Description of selected adverse reactions

In the 5 placebo controlled studies, CHF occurred in the dronedarone group with rates comparable with placebo (very commonly, 11.2% versus 10.9%). This rate should be considered in the context of the underlying elevated incidence of CHF in AF patients. Cases of CHF have also been reported in post-marketing experience (frequency unknown) (see section 4.4).

In the 5 placebo controlled studies, 0.6% of patients in the dronedarone group had pulmonary events versus 0.8% of patients receiving placebo. Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in post-marketing experience (frequency unknown). A number of patients had been previously exposed to amiodarone (see section 4.4).

4.9 Overdose

It is not known whether dronedarone and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

There is no specific antidote available. In the event of overdose, treatment should be supportive and directed toward alleviating symptoms.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antiarrhythmic, ATC code: C01BD07

Mechanism of Action

In animals, dronedarone prevents atrial fibrillation or restores normal sinus rhythm depending on the model used. It also prevents ventricular tachycardia and ventricular fibrillation in several animal models. These effects most likely result from its electrophysiological properties belonging to all four Vaughan-Williams classes. Dronedarone is a multichannel blocker inhibiting the potassium currents (including IK(Ach), IKur, IKr, IKs) and thus prolonging cardiac action potential and refractory periods (Class III). It also inhibits the sodium currents (Class Ib) and the calcium currents (Class IV). It non-competitively antagonises adrenergic activities (Class II).

Pharmacodynamic Properties

In animal models, dronedarone reduces the heart rate. It prolongs Wenckebach cycle length and AH-, PQ-, QT- intervals; with no marked effect or weak increase on QTc-intervals, and with no change in HV- and QRS- intervals. It increases effective refractory periods (ERP) of the atrium, atrio-ventricular node, and ventricular ERP was slightly prolonged with a minimal degree of reverse frequency dependency.

Dronedarone decreases arterial blood pressure and myocardial contractility (dP/dt max) with no change in left ventricular ejection fraction and reduces myocardial oxygen consumption.

Dronedarone has vasodilatory properties, in coronary arteries (related to the activation of the nitric oxide pathway) and in peripheral arteries.

Dronedarone displays indirect antiadrenergic effects and partial antagonism to adrenergic stimulation. It reduces alpha-adrenergic blood pressure response to epinephrine and beta1 and beta2 responses to isoproterenol.

Clinical data

Reduction of risk of AF-related hospitalisation

The efficacy of dronedarone in the reduction of risk of AF-related hospitalisation was demonstrated in patients with AF or a history of AF and additional risk factors in the ATHENA multicenter, multinational, double blind, and randomised placebo-controlled study.

Patients were to have at least one risk factor (including age, hypertension, diabetes, prior cerebrovascular accident, left atrium diameter

Four thousand six hundred and twenty eight (4,628) patients were randomised and treated for up to 30 months maximum (median follow-up: 22 months) with either dronedarone 400 mg twice daily (2,301 patients) or placebo (2,327 patients), in addition to conventional therapy including beta-blockers (71%), ACE inhibitors or AIIRAs (69%) digitalis (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), chronic antiplatelet therapy (6%) and/or diuretics (54%).

The primary endpoint of the study was the time to first hospitalisation for cardiovascular reasons or death from any cause.

Patients ranged in age from 23 to 97 years and 42% were over 75 years old. Forty seven percent (47%) of patients were female and a majority were Caucasian (89%).

The majority had hypertension (86%) and structural heart disease (60%) (including coronary artery disease: 30%; congestive heart failure (CHF): 30% ; LVEF< 45%: 12%).

Twenty five percent (25%) had AF at baseline.

Dronedarone reduced the incidence of cardiovascular hospitalisation or death from any cause by 24.2% when compared to placebo (p<0.0001).

The reduction in cardiovascular hospitalisation or death from any cause was consistent in all subgroups, irrespective of baseline characteristics or medications (ACE inhibitors or AIIRAs; beta-blockers, digitalis, statins, calcium antagonists, diuretics) (see figure 1).

Figure 1 - Relative risk (dronedarone 400 mg twice daily versus placebo) estimates with 95% confidence intervals according to selected baseline characteristics- first cardiovascular hospitalisation or death from any cause.

a Determined from Cox regression model

b P-value of interaction between baseline characteristics and treatment based on Cox regression model

c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil

Similar results were obtained on the incidence of cardiovascular hospitalisation with a risk reduction of 25.5% (p<0.0001).

During the course of the study, the number of deaths from any cause was comparable between the dronedarone (116/2,301) and placebo (139/2,327) groups.

Maintenance of sinus rhythm

In EURIDIS and ADONIS, a total of 1,237 patients with a prior episode of AF or AFL were randomised in an outpatient setting and treated with either dronedarone 400 mg twice daily (n = 828) or placebo (n = 409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or AIIRAs, chronic antiplatelet agents, diuretics, statins, digitalis, and calcium antagonists). Patients had at least one ECG-documented AF/AFL episode during the last 3 months and were in sinus rhythm for at least one hour and were followed for 12 months. In patients who were taking amiodarone, an ECG was to be performed about 4 hours after the first administration to verify good tolerability. Other antiarrhythmic drugs had to be withdrawn for at least 5 plasma half-lives prior to the first administration.

Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (69%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%) including coronary heart disease (21.8%).

In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone consistently delayed the time to first recurrence of AF/AFL (primary endpoint). As compared to placebo, dronedarone lowered the risk of first AF/AFL recurrence during the 12-month study period by 25% (p = 0.00007). The median time from randomised to first AF/AFL recurrence in the dronedarone group was 116 days, i.e. 2.2-fold longer than in the placebo group (53 days).

The DIONYSOS study compared the efficacy and safety of dronedarone (400 mg twice daily) versus amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) over 6 months. A total of 504 patients with documented AF were randomised, 249 received dronedarone and 255 received amiodarone. The incidence of the primary efficacy endpoint defined as first recurrence of AF or premature study drug discontinuation for intolerance or lack of efficacy at 12 months was 75% in the dronedarone group and 59% in the amiodarone group (hazard ratio=1.59, log-rank p-value <0.0001). AF recurrence was 63.5% versus 42%, respectively. Recurrences of AF (including absence of conversion) were more frequent in the dronedarone group, whereas premature study drug discontinuations due to intolerance were more frequent in the amiodarone group. The incidence of the main safety endpoint defined as the occurrence of thyroid, hepatic, pulmonary, neurological, skin, eye or gastrointestinal specific events or premature study drug discontinuation following any adverse event was reduced by 20% in the dronedarone group compared to the amiodarone group (p=0.129). This reduction was driven by the occurrence of significantly fewer thyroid and neurological events and a trend for less skin or ocular events, and fewer premature study drug discontinuations compared to the amiodarone group.

More gastrointestinal adverse events, mainly diarrhoea, were observed in the dronedarone group (12.9% versus 5.1%).

Patients with symptoms of heart failure at rest or with minimal exertion within the previous month prior, or who were hospitalised for heart failure during the previous month.

The ANDROMEDA study was conducted in 627 patients with left ventricular dysfunction, hospitalised with new or worsening heart failure and who had had at least one episode of shortness of breath on minimal exertion or at rest (NYHA class III or IV) or paroxysmal nocturnal dyspnoea within the month before admission.

The study was stopped prematurely due to an observed imbalance of deaths in the dronedarone group [n = 25 versus 12 (placebo), p = 0.027] (see sections 4.3 and 4.4).

Patients with Permanent Atrial Fibrillation:

The PALLAS study was a randomized placebo-controlled study investigating the clinical benefit of dronedarone 400 mg BID on top of standard therapy in patients with permanent atrial fibrillation and additional risk factors (patients with congestive heart failure ~ 69%, coronary heart disease ~ 41%, prior stroke or TIA ~ 27%; LVEF

5.2 Pharmacokinetic Properties

Absorption

Following oral administration in fed condition, dronedarone is well absorbed (at least 70%). However due to presystemic first pass metabolism, the absolute bioavailability of dronedarone (given with food) is 15%. Concomitant intake of food increases dronedarone bioavailability by on average 2- to 4- fold. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state mean dronedarone Cmax is 84-147 ng/ml and the exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0-fold increase with respect to Cmax and AUC.

Distribution

The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5% respectively and is not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state (Vss) ranges from 1,200 to 1,400 l.

Metabolism

Dronedarone is extensively metabolised, mainly by CYP 3A4 (see section 4.5). The major metabolic pathway includes N-debutylation to form the main circulating active metabolite followed by oxidation, oxidative deamination to form the inactive propanoic acid metabolite, followed by oxidation, and direct oxidation. Monoamine Oxidases contribute partially to the metabolism of the active metabolite of dronedarone (see section 4.5).

The N-debutyl metabolite exhibits pharmacodynamic activity but is 3 to 10-times less potent than dronedarone. This metabolite contributes to the pharmacological activity of dronedarone in humans.

Elimination

After oral administration, approximately 6% of the labelled dose is excreted in urine mainly as metabolites (no unchanged compound excreted in urine) and 84% are excreted in faeces mainly as metabolites. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 l/h. The terminal elimination half-life of dronedarone is around 25-30 hours and that of its N-debutyl metabolite around 20-25 hours. In patients, dronedarone and its metabolite are completely eliminated from the plasma within 2 weeks after the end of a 400 mg twice daily- treatment.

Special populations

The pharmacokinetics of dronedarone in patients with AF is consistent with that in healthy subjects. Gender, age and weight are factors that influence the pharmacokinetics of dronedarone. Each of these factors has a limited influence on dronedarone.

Gender

In female patients, dronedarone exposures and its N-debutyl metabolite exposure are on average 1.3 to 1.9-fold higher as compared to male patients.

Elderly

Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over and 34% were 75 years of age and over. In patients aged 65 years of age and over, dronedarone exposures are 23% higher in comparison with patients aged below 65 years of age.

Hepatic impairment

In subjects with moderate hepatic impairment, dronedarone unbound exposure is increased by 2-fold. That of the active metabolite is decreased by 47% (see section 4.2).

The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed (see section 4.3).

Renal impairment

The effect of renal impairment on dronedarone pharmacokinetics has not been evaluated in a specific study. Renal impairment is not expected to modify the pharmacokinetics of dronedarone because no unchanged compound was excreted in urine and only approximately 6% of the dose was excreted in urine as metabolites (see section 4.2).

5.3 Preclinical Safety Data

Dronedarone had no genotoxic effects, based on one in vivo micronucleus test in mice and four in vitro tests.

In 2-year oral carcinogenicity studies, the highest dronedarone dose administered for 24 months was 70 mg/kg/day in rats and 300 mg/kg/day in mice.

Observations were increased incidence of mammary gland tumors in female mice, histiocytic sarcomas in mice and hemangiomas at the mesenteric lymph node level in rats, all at the highest tested dose only (corresponding to an exposure of 5 to 10 times that of the human therapeutic dose). Hemangiomas are not precancerous changes and do not transform into malignant hemangiosarcomas in either animals or man. None of these observations was considered relevant for humans.

In chronic toxicity studies, slight and reversible phospholipidosis (accumulation of foamy macrophages) was observed in mesenteric lymph nodes mainly in the rat. This effect is considered specific to this species and not relevant to humans.

Dronedarone caused marked effects on embryo-foetal development at high doses in rats, such as increased post-implantation losses, reduced foetal and placental weights, and external, v