Resolor 1mg film-coated tablets

1. Name Of The Medicinal Product

Resolor 1 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 1 mg prucalopride (as prucalopride succinate).

Excipients: Each film-coated tablet contains 150 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

White to off-white, round, biconvex tablets marked “PRU 1” on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Resolor is indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.

4.2 Posology And Method Of Administration

Posology

Women: 2 mg once daily.

Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.

Elderly (>65 years): Start with one 1 mg once daily (see section 5.2); if needed the dose can be increased to 2 mg once daily.

Children and adolescents: Resolor is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2.

Patients with renal impairment: The dose for patients with severe renal impairment (GFR < 30 ml/min/1.73 m²) is 1 mg once daily (see sections 4.3 and 5.2). No dose adjustment is required for patients with mild to moderate renal impairment.

Patients with hepatic impairment: The dose for patients with severe hepatic impairment (Child-Pugh class C) is 1 mg once daily (see sections 4.4 and 5.2). No dose adjustment is required for patients with mild to moderate hepatic impairment.

Due to the specific mode of action of prucalopride (stimulation of propulsive motility) exceeding the daily dose of 2 mg is not expected to increase efficacy.

If the intake of once daily prucalopride is not effective after 4 weeks of treatment, the patient should be re-examined and the benefit of continuing treatment reconsidered.

The efficacy of prucalopride has been established in double blind placebo controlled studies for up to 3 months. In case of prolonged treatment the benefit should be reassessed at regular intervals.

Method of administration

Resolor film-coated tablets are for oral use and can be taken with or without food, at any time of the day.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Renal impairment requiring dialysis.

- Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.

4.4 Special Warnings And Precautions For Use

Renal excretion is the main route of elimination of prucalopride (see section 5.2). A dose of 1 mg is recommended in subjects with severe renal impairment (see section 4.2).

Patients with severe and clinically unstable concomitant disease (e.g. liver, cardiovascular or lung disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been studied. Caution should be exercised when prescribing Resolor to patients with these conditions. In particular Resolor should be used with caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.

In case of severe diarrhoea, the efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive).

It is unlikely that hepatic impairment will affect prucalopride metabolism and exposure in man to a clinically relevant extent. No data are available in patients with mild, moderate or severe hepatic impairment, and therefore a lower dose is recommended for patients with severe hepatic impairment (see section 4.2).

Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption must not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products. Although prucalopride may be a weak substrate for P-glycoprotein (P-gp), it is not an inhibitor of P-gp at clinically relevant concentrations.

Ketoconazole (200 mg b.i.d.), a potent inhibitor of CYP3A4 and of P-gp, increased the area under the curve (AUC) of prucalopride by approximately 40%. This effect is too small to be clinically relevant and is likely attributable to inhibition of P-gp mediated renal transport. Interactions of similar magnitude as observed with ketoconazole may also occur with other potent inhibitors of P-gp such as verapamil, cyclosporine A and quinidine. Prucalopride is likely also secreted via another renal transporter(s). Inhibition of all transporters involved in the active secretion of prucalopride (including P-gp) may theoretically increase the exposure by up to 75%.

Studies in healthy subjects showed that there were no clinically relevant effects of prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol and paroxetine. A 30% increase in the plasma concentrations of erythromycin was found during prucalopride co-treatment. The mechanism for this interaction is not fully known, but the available data support that this is the consequence of the high intrinsic variability in erythromycin kinetics, rather than a direct effect of prucalopride.

Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride.

Resolor should be used with caution in patients receiving concomitant drugs known to cause QTc prolongation.

Because of the mechanism of action, the use of atropine-like substances may reduce the 5-HT₄ receptor mediated effects of prucalopride.

Interactions with food have not been observed.

4.6 Pregnancy And Lactation

Pregnancy

Experience with prucalopride during pregnancy is limited. Cases of spontaneous abortion have been observed during clinical studies, although, in the presence of other risk factors, the relationship to prucalopride is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Resolor is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with prucalopride.

Lactation

Prucalopride is excreted in breast milk. However, at therapeutic doses of Resolor no effects on the breastfed newborns/infants are anticipated. In the absence of human data, it is not recommended to use Resolor during breast-feeding.

Fertility

Animal studies indicate that there is no effect on male or female fertility.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of prucalopride on the ability to drive and use machines have been performed. Resolor has been associated with dizziness and fatigue particularly during the first day of treatment which may have an effect on driving and using machines (see section 4.8).

4.8 Undesirable Effects

Resolor has been given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received Resolor at the recommended dose of 2 mg per day, while about 1,300 patients were treated with 4 mg prucalopride daily. Total exposure in the clinical development plan exceeded 2,600 patient years. The most frequently reported adverse reactions associated with Resolor therapy are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea) occurring in approximately 20% of patients each. The adverse reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment. Other adverse reactions have been reported occasionally. The majority of adverse events were mild to moderate in intensity.

The following adverse reactions were reported in controlled clinical studies at the recommended dose of 2 mg with frequencies corresponding to Very common (

Metabolism and nutrition disorders

Uncommon: anorexia

Nervous system disorders

Very common: headache

Common: dizziness

Uncommon: tremors

Cardiac disorders

Uncommon: palpitations

Gastrointestinal disorders

Very common: nausea, diarrhoea, abdominal pain

Common: vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds

Renal and urinary disorders

Common: pollakiuria

General disorders and administration site conditions

Common: fatigue

Uncommon: fever, malaise

After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence less than 1% different between prucalopride and placebo) during Resolor therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during Resolor therapy, but less pronounced (difference in incidence between prucalopride and placebo between 1 and 3%).

Palpitations were reported in 0.7% of the placebo patients, 1.0% of the 1 mg prucalopride patients, 0.7% of the 2 mg prucalopride patients and 1.9% of the 4 mg prucalopride patients. The majority of patients continued using prucalopride. As with any new symptom, patients should discuss the new onset of palpitations with their physician.

4.9 Overdose

In a study in healthy volunteers treatment with prucalopride was well tolerated when given in an up-titrating scheme up to 20 mg once daily (10 times the recommended therapeutic dose). An overdose may result in symptoms resulting from an exaggeration of the medicinal product's known pharmacodynamic effects and include headache, nausea and diarrhoea. Specific treatment is not available for Resolor overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs acting on serotonin receptors, ATC code: A03AE04.

Mechanism of action

Prucalopride is a dihydrobenzofurancarboxamide with enterokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT₄) receptor agonist, which is likely to explain its enterokinetic effects. In vitro, only at concentrations exceeding its 5-HT₄ receptor affinity by at least 150-fold, affinity for other receptors was detected. In rats prucalopride in vivo at doses above 5 mg/kg (at and above 30-70 times the clinical exposure) induced hyperprolactinaemia caused by an antagonistic action at the D2 receptor.

In dogs, prucalopride alters colonic motility patterns via serotonin 5-HT₄ receptor stimulation: it stimulates proximal colonic motility, enhances gastroduodenal motility and accelerates delayed gastric emptying. Furthermore, giant migrating contractions are induced by prucalopride. These are equivalent to the colonic mass movements in humans, and provide the main propulsive force to defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade with selective 5-HT₄ receptor antagonists illustrating that the observed effects are exerted via selective action on 5-HT₄ receptors.

Clinical experience

The efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 females, 155 males). The prucalopride doses studied in each of these three studies included 2 mg and 4 mg once daily. The primary efficacy endpoint was the proportion (%) of subjects that reached normalisation of bowel movements defined as an average of three or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. Both doses were statistically superior (p<0.001) to placebo at the primary endpoint in each of the three studies, with no incremental benefit of the 4 mg over the 2 mg dose. The proportion of patients treated with the recommended dose of 2 mg prucalopride that reached an average of

In all three studies, treatment with prucalopride also resulted in significant improvements in a validated and disease specific set of symptom measures (PAC SYM), including abdominal, stool and rectal symptoms, determined at week 4 and week 12. A significant benefit on a number of Quality of Life measures, such as degree of satisfaction with treatment and with bowel habits, physical and psychosocial discomfort and worries and concerns, was also observed at both the 4 and 12 week assessment time points.

Prucalopride has been shown not to cause rebound phenomena, nor to induce dependency.

A thorough QT study was performed to evaluate the effects of prucalopride on the QT interval at therapeutic (2 mg) and supratherapeutic doses (10 mg) and compared with the effects of placebo and a positive control. This study did not show significant differences between prucalopride and placebo at either dose, based on mean QT measurements and outlier analysis. This confirmed the results of two placebo controlled QT studies. In double blind clinical studies, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo.

Data from open label studies up to 2.6 years offer some evidence for longer-term safety and efficacy; however, no placebo controlled efficacy data for treatments longer than 12 weeks duration are available.

5.2 Pharmacokinetic Properties

Absorption

Prucalopride is rapidly absorbed; after a single oral dose of 2 mg C_max was attained in 2-3 hours. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.

Distribution

Prucalopride is extensively distributed, and has a steady-state volume of distribution (Vd_ss) of 567 litre. The plasma protein binding of prucalopride is about 30%.

Metabolism

Metabolism is not the major route of elimination of prucalopride. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. In an oral dose study with radiolabelled prucalopride in man small amounts of eight metabolites were recovered in urine and faeces. The major metabolite (R107504, formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) accounted for less than 4% of the dose. Unchanged active substance made up about 85% of the total radioactivity in plasma and only R107504 was a minor plasma metabolite.

Elimination

A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. The plasma clearance of prucalopride averages 317 ml/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2 mg prucalopride steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride is dose-proportional within and beyond the therapeutic range (tested up to 20 mg). Prucalopride o.d. displays time-independent kinetics during prolonged treatment.

Special populations

Population pharmacokinetics

A population pharmacokinetic analysis showed that the apparent total clearance of prucalopride was correlated with creatinine clearance, but that age, body weight, sex or race had no influence.

Elderly

After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in elderly subjects were 26% to 28% higher than in young adults. This effect can be attributed to a diminished renal function in elderly.

Renal impairment

Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single 2 mg dose were on average 25% and 51% higher in subjects with mild (Cl_CR 50-79 ml/min) and moderate (Cl_CR 25-49 ml/min) renal impairment, respectively. In subjects with severe renal impairment (Cl_CR

Hepatic impairment

Non-renal elimination contributes to about 35% of total elimination, and hepatic impairment is unlikely to affect the pharmacokinetics of prucalopride to a clinically relevant extent (see section 4.2 and 4.4).

Paediatric population

After a single oral dose of 0.03 mg/kg in paediatric patients aged between 4 and 12 years , C_max of prucalopride was comparable to the C_max in adults after a single 2 mg dose, while unbound AUC was 30-40% lower than after 2 mg in adults. Unbound exposure was similar over the whole age-range (4-12 years).The average terminal half life in the paediatric subjects was about 19 hours (range 11.6 to 26.8 hours) (see section 4.2).

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. An extended series of safety pharmacology studies with special emphasis on cardiovascular parameters showed no relevant changes in haemodynamic and ECG derived parameters (QTc) with the exception of a modest increase in heart rate and blood pressure observed in anaesthesized pigs after intravenous administration, and an increase in blood pressure in conscious dogs after bolus intravenous administration, which was not observed either in anaesthetized dogs or after oral administration in dogs reaching similar plasma levels.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Colloidal silicon dioxide

Magnesium stearate

Coating

Hypromellose

Lactose monohydrate

Triacetin

Titanium dioxide (E171)

Macrogol 3000

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

4 years.

6.4 Special Precautions For Storage

Store in the original blister in order to protect from moisture.

6.5 Nature And Contents Of Container

Aluminium/aluminium perforated unit dose blisters (calendar marked) containing 7 tablets. Each pack contains 7 x 1, 14 x 1, 28 x 1 or 84 x 1 film-coated tablet.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Shire-Movetis NV

Veedijk 58

B-2300 Turnhout

Belgium

Tel.: 008006683 8470

8. Marketing Authorisation Number(S)

EU/1/09/581/001 (28 tablets)

EU/1/09/581/003 (7 tablets)

EU/1/09/581/005 (14 tablets)

EU/1/09/581/007 (84 tablets)

9. Date Of First Authorisation/Renewal Of The Authorisation

15/10/09

10. Date Of Revision Of The Text

October 2011

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

colistin, neomycin, thonzonium, and hydrocortisone Otic

koe-LIS-tin SUL-fate, nee-oh-MYE-sin SUL-fate, hye-droe-KOR-ti-sone AS-e-tate, thon-ZOE-nee-um BROE-mide

Commonly used brand name(s)

In the U.S.

• Coly-Mycin S


• Cortisporin TC

In Canada

• Coly-Mycin

Available Dosage Forms:

• Suspension

Therapeutic Class: Anti-Infective/Anti-Inflammatory Combination

Pharmacologic Class: Hydrocortisone

Chemical Class: Neomycin

Uses For colistin, neomycin, thonzonium, and hydrocortisone

Colistin, neomycin, and hydrocortisone combination contains two antibiotics and a cortisone-like medicine. It is used in the ear to treat infections of the ear canal and to help provide relief from redness, irritation, and discomfort of certain ear problems.

Colistin, neomycin, and hydrocortisone combination is available only with your doctor's prescription.

Before Using colistin, neomycin, thonzonium, and hydrocortisone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For colistin, neomycin, thonzonium, and hydrocortisone, the following should be considered:

Allergies

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

Pediatric

Although there is no specific information comparing use of colistin, neomycin, and hydrocortisone combination in children with use in other age groups, colistin, neomycin, thonzonium, and hydrocortisone is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of colistin, neomycin, and hydrocortisone combination in the elderly with use in other age groups, colistin, neomycin, thonzonium, and hydrocortisone is not expected to cause different side effects or problems in older people than it does in younger adults.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking colistin, neomycin, thonzonium, and hydrocortisone, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using colistin, neomycin, thonzonium, and hydrocortisone with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Rotavirus Vaccine, Live

Using colistin, neomycin, thonzonium, and hydrocortisone with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alcuronium


• Aldesleukin


• Atracurium


• Bupropion


• Cidofovir


• Cisatracurium


• Colistimethate Sodium


• Decamethonium


• Doxacurium


• Ethacrynic Acid


• Fazadinium


• Furosemide


• Gallamine


• Hexafluorenium


• Metocurine


• Mivacurium


• Pancuronium


• Pipecuronium


• Quetiapine


• Rapacuronium


• Rocuronium


• Sorafenib


• Tacrolimus


• Tubocurarine


• Vecuronium

Using colistin, neomycin, thonzonium, and hydrocortisone with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alatrofloxacin


• Alcuronium


• Atracurium


• Balofloxacin


• Bumetanide


• Cinoxacin


• Ciprofloxacin


• Clinafloxacin


• Colestipol


• Enoxacin


• Fleroxacin


• Flumequine


• Gallamine


• Gemifloxacin


• Grepafloxacin


• Hexafluorenium


• Itraconazole


• Levofloxacin


• Licorice


• Lomefloxacin


• Metocurine


• Moxifloxacin


• Norfloxacin


• Ofloxacin


• Pefloxacin


• Primidone


• Prulifloxacin


• Rifapentine


• Rosoxacin


• Rufloxacin


• Saiboku-To


• Sparfloxacin


• Temafloxacin


• Tosufloxacin


• Trovafloxacin Mesylate

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

The presence of other medical problems may affect the use of colistin, neomycin, thonzonium, and hydrocortisone. Make sure you tell your doctor if you have any other medical problems, especially:

• Other ear infection or problem, including punctured eardrum—Use of colistin, neomycin, and hydrocortisone combination may make the condition worse or may increase the chance of side effects

• Herpes simplex—Use of hydrocortisone may make the condition worse

Proper Use of colistin, neomycin, thonzonium, and hydrocortisone

Before applying colistin, neomycin, thonzonium, and hydrocortisone, thoroughly clean the ear canal and dry it with a sterile cotton applicator.

You may warm the ear drops to body temperature (37 °C or 98.6 °F), but no higher, by holding the bottle in your hand for a few minutes before applying. If colistin, neomycin, thonzonium, and hydrocortisone gets too warm, it may break down and not work properly.

To apply colistin, neomycin, thonzonium, and hydrocortisone:

• Lie down or tilt the head so that the infected ear faces up. Gently pull the earlobe up and back for adults (down and back for children) to straighten the ear canal. Drop the medicine into the ear canal. Keep the ear facing up for about 5 minutes to allow the medicine to coat the ear canal. (For young children and other patients who cannot stay still for 5 minutes, try to keep the ear facing up for at least 1 or 2 minutes.) Your doctor may have inserted a gauze or cotton wick into your ear and may want you to keep the wick moistened with colistin, neomycin, thonzonium, and hydrocortisone. Your doctor also may have other directions for you, such as how long you should keep the wick in your ear or when you should return to your doctor to have the wick replaced. If you have any questions about this, check with your doctor.

To keep the medicine as germ-free as possible, do not touch the dropper to any surface (including the ear). Also, keep the container tightly closed.

Do not use colistin, neomycin, thonzonium, and hydrocortisone for more than 10 days unless otherwise directed by your doctor.

To help clear up your infection completely, keep using colistin, neomycin, thonzonium, and hydrocortisone for the full time of treatment, even if your symptoms begin to clear up after a few days. If you stop using colistin, neomycin, thonzonium, and hydrocortisone too soon, your symptoms may return. Do not miss any doses.

Dosing

The dose of colistin, neomycin, thonzonium, and hydrocortisone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of colistin, neomycin, thonzonium, and hydrocortisone. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For otic suspension (ear drops) dosage form:
  
  • For infections of the ear canal:
    
    • Adults—Use four drops in the ear every six to eight hours.
    
    
    • Children—Use up to three drops in the ear every six to eight hours.
    
    
  
  

Missed Dose

If you miss a dose of colistin, neomycin, thonzonium, and hydrocortisone, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using colistin, neomycin, thonzonium, and hydrocortisone

If your symptoms do not improve within 1 week, or if they become worse, check with your doctor immediately.

colistin, neomycin, thonzonium, and hydrocortisone Side Effects

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

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

More common

• Itching, skin rash, redness, swelling, or other sign of irritation not present before use of colistin, neomycin, thonzonium, and hydrocortisone

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More colistin, neomycin, thonzonium, and hydrocortisone Otic resources

• Colistin, neomycin, thonzonium, and hydrocortisone Otic Use in Pregnancy & Breastfeeding
• Colistin, neomycin, thonzonium, and hydrocortisone Otic Drug Interactions
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Ritalin

1. Name Of The Medicinal Product

Ritalin^®

2. Qualitative And Quantitative Composition

The active ingredient is Methylphenidate (INN for α-Phenyl-2-piperidineacetic acid methyl ester hydrochloride).

One tablet contains 10mg methylphenidate hydrochloride.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Ritalin is indicated as a part of a comprehensive treatment programme for attention-deficit hyperactivity disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. Treatment must be under the supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to DSM-IV criteria or the guidelines in ICD-10 and should be based on a complete history and evaluation of the patient. Diagnosis cannot be made solely on the presence of one or more symptom.

The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and specialised psychological, educational and social resources.

A comprehensive treatment programme, typically includes psychological, educational and social measures as well as pharmacotherapy and is aimed at stabilising children with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired.

Methylphenidate treatment is not indicated in all children with this syndrome and the decision to use the drug must be based on a very thorough assessment of the severity and the chronicity of the child's symptoms in relation to the child's age.

Appropriate educational placement is essential, and psychosocial intervention is generally necessary. Where remedial measures alone prove insufficient, the decision to prescribe a stimulant must be based on rigorous assessment of the severity of the child's symptoms. The use of methylphenidate should always be used in the way according to the licensed indication and according to the prescribing/diagnostics guidelines.

4.2 Posology And Method Of Administration

Treatment must be initiated under the supervision of a specialist in childhood and/or adolescent behavioural disorders

Pre-treatment screening:

Prior to prescribing, it is necessary to conduct a baseline evaluation of a patient's cardiovascular status including blood pressure and heart rate. A comprehensive history should document concomitant medications, past and present co-morbid medical and psychiatric disorders or symptoms, family history of sudden cardiac/unexplained death and accurate recording of pre-treatment height and weight on a growth chart (see sections 4.3 and 4.4).

Ongoing monitoring:

Growth, psychiatric and cardiovascular status should be continuously monitored (see section 4.4).

• Blood pressure and pulse should be recorded on a centile chart at each adjustment of dose and then at least every 6 months;

• Height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart;

• Development of de novo or worsening of pre-existing psychiatric disorders should be monitored at every adjustment of dose and then at least every 6 months and at every visit.

Patients should be monitored for the risk of diversion, misuse and abuse of methylphenidate.

Dose titration

Careful dose titration is necessary at the start of treatment with methylphenidate. Dose titration should be started at the lowest possible dose.

The maximum daily dose is 60mg.

Other strengths of this medicinal product and other methylphenidate containing products may be available.

Children: (over 6 years). Begin with 5mg once or twice daily (e.g. at breakfast and lunch), increasing the dose and frequency of administration if necessary by weekly increments of 5-10mg in the daily dose. Doses above 60mg daily are not recommended. The total daily dose should be administered in divided doses. Ritalin is not indicated in children less than 6 years of age.

If the effect of the drug wears off too early in the evening, disturbed behaviour and/or inability to go to sleep may recur. A small evening dose may help to solve this problem.

Long term (more than 12 months) use in children and adolescents

The safety and efficacy of long term use of methylphenidate has not been systematically evaluated in controlled trials. Methylphenidate treatment should not and need not, be indefinite. Methylphenidate treatment is usually discontinued during or after puberty. The physician who elects to use methylphenidate for extended periods (over 12 months) in children and adolescents with ADHD should periodically re-evaluate the long term usefulness of the drug for the individual patient with trial periods off medication to assess the patient's functioning without pharmacotherapy. It is recommended that methylphenidate is de-challenged at least once yearly to assess the child's condition (preferable during school holidays). Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Dose reduction and discontinuation

Treatment must be stopped if the symptoms do not improve after appropriate dosage adjustment over a one-month period. If paradoxical aggravation of symptoms or other serious adverse events occur, the dosage should be reduced or discontinued.

Adults

Methylphenidate is not licensed for use in adults with ADHD. Safety and efficacy have not yet been established in this age group.

Elderly

Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group.

Children under 6 years of age

Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

4.3 Contraindications

• Known sensitivity to methylphenidate or to any of the excipients in Ritalin.

• Glaucoma

• Phaechromocytoma

• During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those drugs, due to risk of hypertensive crisis (see section 4.5)

• Hyperthyroidism or thyrotoxicosis

• Diagnosis or history of severe depression, anorexia nervosa/anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic/borderline personality disorder.

• Diagnosis or history of severe and episodic (Type 1) Bipolar (affective) disorder (that is not well controlled)

• Pre-existing cardiovascular disorders including severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels)

• Pre-existing cerebrovascular disorders cerebral aneurysm, vascular abnormalities including vasculitis or stroke or known risk factors for cerebrovascular disorders

4.4 Special Warnings And Precautions For Use

Methylphendate treatment is not indicated in all children with ADHD and the decision to use the drug must be based on a very thorough assessment of the severity and chronicity of the child's symptoms in relation to the child's age.

Long term use (more than 12 months) in children and adolescents

The safety and efficacy of long term use of methylphenidate has not been systematically evaluated in controlled trials. Methylphenidate treatment should not and need not be indefinite. Methylphenidate treatment is usually discontinued during or after puberty. Patients on long-term therapy (i.e. over 12 months) must have careful ongoing monitoring according to the guidance in section 4.2 and 4.4 for cardiovascular status, growth, appetite, development of de nevo or worsening of pre-existing psychiatric disorders. Psychiatric disorders to monitor for are described below, and include (but are not limited to) motor or vocal tics, aggressive or hostile behaviour, agitation, anxiety, depression, psychosis, mania, delusions, irritability, lack of spontaneity, withdrawal and excessive perseveration.

The physician who elects to use methylphenidate for extended periods (over 12 months) in children and adolescents with ADHD should periodically re-evaluate the long term usefulness of the drug for the individual patient with trial periods off medication to assess the patient's functioning without pharmacotherapy. It is recommended that methylphenidate is de-challenged at least once yearly to assess the child's condition (preferably during times of school holidays). Improvement may be sustained when the drug is either temporary or permanently discontinued.

Use in adults

Methylphenidate is not licenced for use in adults with ADHD. Safety and efficacy have not yet been established in this age group.

Use in the Elderly

Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group.

Use in children under 6 years of age

Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

Cardiovascular status

Patients who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant arrthymia) and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease. Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during methylphenidate treatment should undergo a prompt specialist cardiac evaluation.

Analyses of data from clinical trials of methylphenidate in children and adolescents with ADHD showed that patients using methylphenidate may commonly experience changes in diastolic and systolic blood pressure of over 10 mmHg relative to controls. The short and long term clinical consequences of these cardiovascular effects in children and adolescents are not known, but the possibility of clinical complications cannot be excluded as a result of the effects observed in the clinical trial data. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. See section 4.3 for conditions in which methylphenidate treatment is contraindicated.

Cardiovascular status should be carefully monitored. Blood pressure and pulse should be recorded on centile chart at each adjustment of dose and then at least every 6 months.

The use of methylphenidate is contraindicated in certain pre-existing cardiovascular disorders unless specialist paediatric advice has been obtained (see section 4.3 Contraindications).

Sudden death and pre-existing cardiac structural abnormalities or other serious cardiac disorders

Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children, some of whom had structural cardiac abnormalities or other serious heart problems.

Although some serious heart problems alone may carry an increased risk of sudden death, stimulant products are not recommended in children or adolescents with known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medicine.

Misuse and Cardiovascular Events: Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events.

Cerebrovascular disorders:

See section 4.3 for cerebrovascular conditions in which methylphenidate treatment is contraindicated. Patients with additional risk factors (such as a history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with methylphenidate.

Cerebral vasculitis appears to be very rare idiosyncratic reaction to methylphenidate exposure. There is little evidence to suggest that patients at higher risk can be identified and the initial onset of symptoms may be the first indication of an underlying clinical problem. Early diagnosis, based on a high index of suspicion, may allow the prompt withdrawal of methylphenidate and early treatment. The diagnosis should therefore be considered in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during methylphenidate therapy. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of coordination, vision, speech, language or memory.

Treatment with methylphenidate is not contraindicated in patients with hemiplegic cerebral palsy

Psychiatric disorders

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric disorders, methylphenidate should not be given unless the benefits outweigh the risks to the patient.

Development or worsening of psychiatric disorders should be monitored at every adjustment of dose, then at least every 6 months, and at every visit: discontinuation of treatment may be appropriate.

Exacerbation of pre-existing psychotic or manic symptoms

In psychotic patients, administration of methylphenidate may exacerbate symptoms of behavioural disturbance and thought disorder.

Emergence of new psychotic or manic symptoms

Treatment-emergent psychotic symptoms (visual/tactile/auditory hallucinations and delusions) or mania in children and adolescents without prior history of psychotic illness or mania can be caused by methylphenidate at usual doses. If manic or psychotic symptoms occur, consideration should be given to a possible causal role for methylphenidate and discontinuation of treatment may be appropriate.

Aggressive or hostile behaviour

The emergence or worsening of aggression or hostility can be caused by treatment with stimulants. Patients treated with methylphenidate should be closely monitored for the emergence or worsening of aggressive behaviour or hostility at treatment initiation, at every dose adjustment and then least every 6 months and every visit. Physicians should evaluate the need for adjustment of the treatment regimen in patients experiencing behavioural changes bearing in mind that upwards or downwards tritration may be appropriate. Treatment interruption can be considered.

Suicidal tendency

Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their physician. Consideration should be given to the exacerbation of an underlying psychiatric condition and to a possible causal role of methylphenidate treatment. Treatment of an underlying psychiatric condition may be necessary and consideration should be given to a possible discontinuation of methylphenidate.

Tics

Methylphenidate is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported. Family history should be assessed and clinical evaluation for tics or Tourette's syndrome in children should precede use of methylphenidate. Patients should be regularly monitored for the emergence or worsening of tics during treatment with methylphenidate. Monitoring should be at every adjustment of dose and then at least every 6 months or every visit.

Anxiety, agitation or tension

Methylphenidate is associated with the worsening of pre-existing anxiety, agitation or tension. Clinical evaluation for anxiety, agitation or tension should precede use of methylphenidate and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 months or every visit.

Forms of bipolar disorder

Particular care should be taken in using methylphenidate to treat ADHD in patients with co morbid bipolar disorder (including untreated type 1 bipolar disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with methylphenidate, patients with co morbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients (see above 'Psychiatric Disorders' and section 4.2). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Growth

Moderately reduced weight gain and growth retardation have been reported with long-term use of methylphenidate in children.

The effects of methylphenidate on final height and final weight are currently unknown and being studied.

Growth should be monitored during methylphenidate treatment: height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Seizures

Methylphenidate should be used with caution in patients with epilepsy. Methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and rarely in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new-onset seizures occur, methylphenidate should be discontinued.

Abuse, misuse and diversion

Patients should be carefully monitored for the risk of diversion, misuse and abuse of methylphenidate.

Methylphenidate should be used with caution in patients with known drug or alcohol dependency because of a potential for abuse, misuse or diversion.

Chronic abuse of methylphenidate can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially in response to parenteral abuse.

Patient age, the presence of risk factors for substance use disorder (such as co-morbid oppositional-defiant or conduct disorder and bipolar disorder), previous or current substance abuse should be taken in to account when deciding on a course of treatment for ADHD. Caution is called for in emotionally unstable patients, such as those with a history of drug or alcohol dependence, because such patients may increase the dosage on their own initiative.

For some high-risk substance abuse patients, methylphenidate or other stimulants may not be suitable and non-stimulant treatment should be considered.

Withdrawal

Careful supervision is required during withdrawal, since this may unmask depression as well as chronic over-activity. Some patients may require long-term follow-up.

Careful supervision is required during withdrawal from abusive use since severe depression may occur.

Fatigue

Methylphenidate should not be used for the prevention or treatment of normal fatigue states.

Excipients: glactose/sucrose intolerance

This medicinal product contains lactose: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-glactose malabsorption should not take this medicine.

Choice of methylphenidate formulation

The choice of formulation of methylphenidate-containing product will have to be decided by the treating specialist on an individual basis and depends on the intended duration of effect.

Drug screening

This product contains methylphenidate which may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.

Renal or hepatic insufficiency

There is no experience with the use of methylphenidate in patients with renal or hepatic insufficiency.

Haematological effects

The long-term safety of treatment with methylphenidate is not fully known. In the event of leucopenia, thrombocytopenia, anaemia or other alterations, including those indicative of serious renal or hepatic disorders, discontinuation of treatment should be considered.

Potential for gastrointestinal obstruction

Because Ritalin tablet is nondeformable and does not appreciably change in shape in the gastrointestinal (GI) tract, it should not ordinarily be administered to patients pre-existing severe GI narrowing (pathologic or iatrogenic) or in patients with dsyphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable prolonged-release formulations.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacokinetic interaction

It is not known how methylphenidate may effect plasma concentrations of concomitantly administered drugs. Therefore, caution is recommended at combining methylphenidate with other drugs, especially those with narrow therapeutic window.

Methylphenidate is not metabolised by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and I- enantiomers of methylphenidate do not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

However, there are reports indicating that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g. Phenobarbitol, phenytoin, primodone), and some antidepressants (tricyclic and selective serotonin reuptake inhibitors).

When starting and stopping treatment with methylphenidate, it may be necessary to adjust the dosage of these drugs already being taken and establish drug plasma concentrations (or for coumarin, coagulation times).

Pharmacodynamics interactions

Anti-hypertensive drugs

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.

Use with drugs that elevate blood pressure

Caution is advised in patients being treated with methylphenidate with other drugs that can also elevate blood pressure (see also sections on cardiovascular and cerebrovascular conditions in section 4.4 Warnings and precautions for use).

Because of possible hypertensive crisis, methylphenidate is contraindicated in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO-inhibitors (see section 4.3 Contraindications).

Use with alcohol

Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment

Use with halogenated anaesthetics

There is a risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate treatment should not be used on the day of surgery.

Use with centrally acting alpha-2agonists (e.g. clonidine)

Serious adverse events, including sudden death, have been reported in concomitant use with clonidine. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.

Use with dopaminergic drugs

Caution is recommended when administering methylphenidate with dopaminergic drugs, including antipsychotics. Because a predominant action of methylphenidate is to increase extra cellular dopamine levels, methylphenidate may be associated with pharmacodynamic interactions when co-administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) or with dopamine antagonists including antipsychotics.

4.6 Pregnancy And Lactation

Pregnancy

There is limited amount of data from the use of methylphenidate in pregnant women.

Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported in spontaneous reports.

Studies in animals have only shown evidence of reproductive toxicity at maternally toxic doses. (See Section 5.3, Preclinical Safety Data).

Methylphenidate is not recommended for use during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy.

Lactation

Methylphenidate has been found in breast-milk of a women treated with methylphenidate.

There is one case report of an infant who experienced an unspecified decrease in weight during the period of exposure but recovered and gained weight after the mother discontinued treatment with Methylphenidate. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from methylphenidate 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

Ritalin may cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision. It may have a moderate influence on the ability to drive and use machines. Patients should be warned of these possible effects and advised that if affected, they should avoid potentially hazardous activities such as driving or operating machinery.

4.8 Undesirable Effects

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and post market spontaneous reports with methylphenidate and those, which have been reported with other methylphenidate hydrochloride formulations. If ADRs with methylphenidate and the methylphenidate formulation frequencies were different, the highest frequency of both databases was used.

Frequency estimate: very common (

Infections and infestations

Common: Nasopharyngitis

Blood and lymphatic disorders

Very rare: Anaemia, leucopenia, thrombocytopenia, thrombocytopenic purpura

Unknown: Pancytopenia

Immune system disorders

Uncommon: hypersensitivity reactions such as angioneurotic oedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticaria, pruritis, rashes and eruptions

Metabolism and nutritional disorders *

Common: anorexia, decreased appetite, moderately reduced weight and height gain during prolonged use in children

Psychiatric disorders *

Very common: insomnia, nervousness

Common: anorexia, affect lability, aggression*, agitation*, anxiety*, depression*, irritability, abnormal behaviour

Uncommon: psychotic disorders*, auditory, visual, and tactile hallucinations*, anger, suicidal ideation*, mood altered, mood swings, restlessness, tearfulness, tics*, worsening of pre-existing tics or Tourette's syndrome*, hypervigilance, sleep disorder

Rare: mania*, disorientation, libido disorder

Very rare: suicidal attempt (including completed suicide)*, transient depressed mood*, abnormal thinking, apathy, repetitive behaviours, over-focusing,

Not known: delusions*, thought disturbances*, confessional state, dependence.

Cases of abuse and dependence have been described, more often with immediate release formulations (frequency not known)

Nervous system disorders:

Very common: Headache

Common:, Dizziness, dyskinesia, psychomotor hyperactivity, somnolence

Uncommon: Sedation, tremor

Very rare: Convulsions, choreo-athetoid movements, reversible ischaemic neurological deficit, neuroleptic malignant syndrome (NMS: Reports were poorly documented and in most cases, patients were also receiving other drugs, so the role of methylphenidate is unclear).

Not known: Cerebrovascular disorders * (including vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebral occlusion), grand mal convulsions*, migraine

Eye disorders

Uncommon: Diplopia, blurred vision

Rare: Difficulties in visual accommodation, mydriasis, visual disturbance

Cardiac disorders*

Common: Arrhythmia, tachycardia palpitations

Uncommon: Chest pain

Rare: Angina pectoris

Very rare: Cardiac arrest, myocardial infarction

Not known: Supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles

Vascular disorders*

Common: Hypertension

Very rare: Cerebral arteritis and/or occlusion, peripheral coldness, Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Common: Cough, pharyngolaryngeal pain

Uncommon: dyspnoea

Gastro-intestinal disorders:

Common: Abdominal pain, diarrhoea, nausea, stomach discomfort and vomiting. These usually occur at the beginning of treatment and may be alleviated by concomitant food intake. Dry mouth.

Uncommon: Constipation

Hepatobiliary disorders

Uncommon: Hepatic enzyme elevations

Very rare: Abnormal liver functions, including hepatic coma

Skin and subcutaneous tissue disorders

Common: Alopecia, pruritis, rash, urticaria

Uncommon: Angioneurotic oedema, bullous conditions, exfoliate conditions

Rare: Hyperhidrosis, macular rash, erythema

Very rare: erythema multiforme, exfoliate dermatitis, fixed drug eruption

Musculoskeletal, connective tissue and bone disorders

Common: Arthralgia

Uncommon:Myalgia, muscle twitching

Very rare: Muscle cramps

Renal and urinary disorders

Uncommon: Haematuria

Reproductive system and breast disorders

Rare: Gynaecomastia

General disorders and administration site conditions

Common: Pyrexia, growth retardation during prolonged use in children*

Uncommon: Chest pain, fatigue

Very rare: Sudden cardiac death*

Not known: Chest discomfort, hyperpyrexia

Investigations

Common: Changes in blood pressure and heart rate (usually an increase)*, weight decreased*

Uncommon: Cardiac murmur*, hepatic enzyme increased

Very rare: Blood alkaline phosphatase increased, blood bilirubin increased, platelet count decreased, white blood count abnormal

* See section 4.4 “Special warnings and precautions for use”

4.9 Overdose

When treating patients with overdose, allowances must be made for the delayed release of methylphenidate from formulations with extended durations of action.

Signs and symptoms

Acute overdose, mainly due to overstimulation of the central and sympathetic nervous systems, may result in vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.

Treatment

There is no specific antidote to methylphenidate overdosage.

Treatment consists of appropriate supportive measures.

The patient must be protected against self-injury and against external stimuli that would aggravate over-stimulation already present. If the signs and symptoms are not too severe and the patient is conscious, gastric contents may be evacuated by induction of vomiting or gastric lavage. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. In the presence of severe intoxication, a carefully titrated dose of a benzodiazepine should be given before performing gastric lavage.

Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required to reduce hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdose of methylphenidate has not been established.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: psychostimulants - ATC code: NO6B AO4.

Mode of action: Methylphenidate is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood but its effects are thought to be due to an inhibition of dopamine reuptake in the striatum, without triggering the release of dopamine.

The mechanism by which methylphenidate exerts its mental and behavioural effects in children is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system.

Methylphenidate is a racemic mixture containing d- and I-enantiomers, where the d-enantiomer is considered as the pharmacologically active enantiomer.

5.2 Pharmacokinetic Properties

Absorption:

The active substance methylphenidate hydrochloride is rapidly and almost completely absorbed from the tablets. Owing to extensive first-pass metabolism the absolute bioavailability was 22±8 % for the d-enantiomer and 5±3 % for the l-enantiomer. Ingestion together with food increased both the peak plasma concentration(C_max) by 23% and the area under the concentration-time curve (AUC) by 15%, but had no effect on the rate of absorption has no relevant effect on absorption of methylphenidate.Peak plasma concentrations of approximately 40nmol/litres (11ng/ml) are attained, on average, 1-2 hours after administration of 0.30mg/kg. The peak plasma concentrations, however, show considerable intersubject variability. The AUC and the Cmax, are proportional to the dose.

Distribution:

In the blood, methylphenidate and its metabolites become distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate and its metabolites have a low plasma protein-binding rate (10-33%). The volume of distribution was 2.65±1.11 L/kg for d-MPH and 1.80±0.91 L/kg for l-MPH.

Biotransformation

Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive. Peak plasma concentrations of α-phenyl-2-piperidyl acetic acid (ritalinic acid) (PPAA) are attained approximately 2 hours after administration of methylphenidate and are 30-50 times higher than those of the unchanged substance. The half-life of PPAA is roughly twice as long as that of methylphenidate, and the mean systemic clearance is 0.17 litres/h/kg. Only small amounts of hydroxylated metabolites (e.g. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.

Elimination:

Methylphenidate is eliminated from the plasma with a mean half-life of 2 hours, The systemic clearance is 0.40±0.12 L/h/kg for d-MPH and 0.73±0.28 L/h/kg for l-MPH. Within 48-96 hours 78-97% of the dose administered is excreted in the urine and 1-3% in the faeces in the form of metabolites. Unchanged methylphenidate appears in the urine only in small quantities (<1%). The bulk of the dose is excreted in the urine as PPAA, (60-86%).

Characteristics in patients:

There are no apparent differences in the pharmacokinetic behaviour of methylphenidate in hyperactive children and healthy adult volunteers.

Elimination data from patients with normal renal function suggest that renal excretion of the unchanged methylphenidate would hardly be diminished at all in the presence of impaired renal function. However, renal excretion of PPAA may be reduced.

5.3 Preclinical Safety Data

Carcinogenicity

In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.

Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.

Pregnancy-embryonal/foetal development

Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The tablets also contain calcium phosphate tribasic special, lactose, wheat starch, gelatin, magnesium stearate and talc.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

Medicines should be kept out of reach of children.

6.5 Nature And Contents Of Container

Ritalin tablets are available in blister packs of 30 tablets in PA/AL/PVC blisters backed with aluminium foil.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Limited

Trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR.

8. Marketing Authorisation Number(S)

PL 00101/0539

9. Date Of First Authorisation/Renewal Of The Authorisation

31 October 1997 / 20 April 2004

10. Date Of Revision Of The Text

12 May 2011

LEGAL CATEGORY

POM

Cyclo-Progynova 2mg

1. Name Of The Medicinal Product

Cyclo-Progynova® 2mg.

2. Qualitative And Quantitative Composition

White Tablets	-	2mg estradiol valerate
Pale Brown Tablets	-	500 micrograms norgestrel
		2mg estradiol valerate

3. Pharmaceutical Form

Sugar-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in perimenopausal and postmenopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. (See Section 4.4 Special Warnings & Special Precautions for Use).

4.2 Posology And Method Of Administration

Cyclo-Progynova is a cyclic HRT product. One tablet is to be taken orally once a day for 21 days, followed by a 7 day tablet free interval. Therefore each new pack is started after a 28 day cycle. The white tablets should be taken from days 1 to 11 followed by the brown tablets from days 12 to 21. It is recommended that the tablets are taken at the same time every day.

For initiation and continuation of treatment of peri- and post-menopausal symptoms the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

For the prevention of osteoporosis Cyclo-Progynova 2mg should be used.

For women still having periods, the first tablet should be taken on the 5^th day of their menstrual period. If menstruation has stopped, or is infrequent or sporadic, then the first tablet can be taken any time.

If the patient is being transferred from a continuous HRT product, the patient may start Cyclo-Progynova on any convenient day. For those transferring from a cyclic or sequential product, Cyclo-Progynova should be started following completion of the previous regimen.

If a tablet is missed, it should be taken as soon as possible, unless it is more than 12 hours late. In this case the missed tablet should be left in the pack and the next tablet taken at the right time. Missing a dose may result in breakthrough bleeding or spotting.

Unless there is a previous diagnosis of endometriosis, it is not recommended that progestagen-containing HRT be given to hysterectomised women.

4.3 Contraindications

- known, past or suspected breast cancer

- known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)

- acute liver disease or a history of liver disease unless liver function tests have returned to normal

- undiagnosed genital bleeding

- untreated endometrial hyperplasia

- previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism)

- active or recent arterial thomboembolic disease (e.g. angina, myocardial infarction)

- known hypersensitivity to the active substances or to any of the excipients

- porphyria

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical Examination/Follow-up:

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical examination (including pelvic and breast) should be guided by this and by the contraindications (section 4.3) and warnings for use (section 4.4). During treatment periodic check-ups are recommended of a frequency and nature dependent on the clinical needs of the individual. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Before starting treatment, pregnancy should be excluded. If withdrawal bleeding fails to occur at about 28-day intervals, the possibility of pregnancy should be considered in peri-menopausal women.

The patient may experience blood loss after completing each pack.

Conditions that need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely monitored. It should be taken into account that these conditions may recur or may be aggravated during treatment with Cyclo-Progynova 2mg, in particular:

- leiomyoma (uterine fibroids) or endometriosis

- a history of, or risk factors for thromboembolic disorders (see below)

- risk factors for oestrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

- hypertension

- liver disorders (e.g. liver adenoma)

- diabetes mellitus with or without vascular involvement

- cholelithiasis

- migraine or severe headache

- systemic lupus erythematosus

- a history of endometrial hyperplasia (see below)

- epilepsy

- asthma

- otosclerosis

- hereditary angioedema

Reasons for immediate withdrawal of therapy

Therapy should be immediately discontinued in the following situations:

- contraindications are discovered

- significant increase in blood pressure

- pregnancy

- jaundice or deterioration in liver function.

- migrainous headaches occur for the first time

Endometrial Hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for 10 days per cycle in non-hysterectomised women reduces, but does not eliminate, this risk.

Breakthrough bleeding and spotting may occur during the first few months of treatment, but if this occurs after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. This may include an endometrial biopsy to exclude endometrial malignancy.

Breast Cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of having breast cancer diagnosed in women taking oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous Thromboembolism (VTE)

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal or family history, severe obesity (Body Mass Index >30 kg/m²) and systemic lupus erythmatosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a risk of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.

If VTE develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of leg, sudden pain in chest, dyspnoea)

Coronary Arterial Disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50–59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT's confers to a different risk than oestrogen-only products.

Other Conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed since it is expected that the level of circulating active ingredients of Cyclo-Progynova may increase.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

Oestrogens increase thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay), or T3 levels (by radio-immunoassay). T3 resin uptake is decreased reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Hormonal contraception should be stopped when treatment with Cyclo-Progynova is started and the patient should be advised to take non-hormonal contraceptive precautions.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestagens.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased efficacy and changes in uterine bleeding profile

The requirement for oral antidiabetics or insulin can change.

4.6 Pregnancy And Lactation

Cyclo-Progynova is not indicated during pregnancy or lactation.

If pregnancy occurs during medication with Cyclo-Progynova treatment should be withdrawn immediately. No data on exposed pregnancies are available. Studies in animals have not shown reproductive toxicity.

The results of most epidemiological studies to-date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

During the first few months treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment.

The following symptoms have been reported during use of Cyclo-Progynova:

Reproductive System – breast tenderness, breast enlargement, breakthrough bleeding, spotting

Gastrointestinal System – increased appetite, bloating, nausea, vomiting, dyspepsia

Skin Disorders – rashes

Nervous System – anxiety, depressive symptoms, dizziness, altered libido, headache

Other – altered weight, oedema, leg cramps, palpitations

Other reactions have also been reported in association with oestrogen/ progestagen treatment:

- Oestrogen-dependent neoplasms benign and malignant, e.g. breast* (see below) and endometrial** (see below) cancer

- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use

- Myocardial infarction and stroke

- Gall bladder disease

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

- Probable dementia (see Section 4.4)

- In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Breast Cancer

* According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21-1.49) and 1.30 (95%CI 1.21-1.40), respectively.

For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of oestrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

        • For users of oestrogen-only replacement therapy

          between 0 and 3 (best estimate = 1.5) for 5 years' use

          between 3 and 7 (best estimate = 5) for 10 years' use.

        • For users of oestrogen plus progestagen combined HRT,

          between 5 and 7 (best estimate = 6) for 5 years' use

          between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).'

Endometrial Cancer

** In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.

4.9 Overdose

There have been no reports of ill-effects from overdosage. There are no specific antidotes, and therefore treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cyclo-Progynova contains synthetic estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol) and the synthetic progestagen, Norgestrel.

Estradiol valerate, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.

As oestrogens promote growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Oestrogens prevent bone loss following menopause or ovariectomy.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT alone or in combination with progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for this is limited.

5.2 Pharmacokinetic Properties

Following oral administration to man, estradiol valerate is rapidly and completely absorbed by the gastrointestinal tract. It is metabolised during absorption and the first pass through the liver into estradiol and its metabolites estrone and estriol. The systemic bioavailability of estradiol is approximately 3% of the dose. The metabolites are mainly excreted in the urine, about 10% of the dose being excreted in the faeces.

Following a single administration of 2 mg orally, a peak estradiol plasma concentration of approximately 50-65 pg/ml is achieved after 3-6 hours. This plasma level may remain elevated for up to 48 hours. Due to daily administration with Cyclo-Progynova the serum levels of estradiol may reach 100-150 pg/ml.

Norgestrel is similarly absorbed from the gastrointestinal tract, metabolised by the liver and excreted in the urine and faeces as glucuronide and sulphate conjugates.

After termination of treatment the estradiol and norgestrel serum levels drop to baseline values within 2 days.

5.3 Preclinical Safety Data

There are no preclinical safety data which could be of relevance to the prescriber and which is not already included in other relevant sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, maize starch, povidone, talc, magnesium stearate [E572], sucrose, calcium carbonate [E170], polyethylene glycol 6000, montan glycol wax, titanium dioxide [E171], yellow ferric oxide [E172], red brown ferric oxide [E172], glycerin.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Not applicable.

6.5 Nature And Contents Of Container

Cardboard outer containing either: one rectangular blister pack or three rectangular blister packs. Each pack consists of aluminium foil and PVC and contains 21 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0067

9. Date Of First Authorisation/Renewal Of The Authorisation

20 10 02

10. Date Of Revision Of The Text

14 March 2011