Boots Maximum Strength Cold & Flu Relief Direct Dose Lemon

1. Name Of The Medicinal Product

Boots Maximum Strength Cold & Flu Relief Direct Dose Lemon

2. Qualitative And Quantitative Composition

Active ingredients	mg/sachet
Paracetamol	1000.0
Phenylephrine hydrochloride	* 12.2

*This is equivalent to 10mg phenylephrine base.

For excipients, see 6.1.

3. Pharmaceutical Form

Oral powder

A white to off-white unit-dose powder with the odour and flavour of lemons.

4. Clinical Particulars

4.1 Therapeutic Indications

For relief of symptoms associated with the common cold and influenza, including the relief of aches and pains, sore throat, headache, nasal congestion and lowering of temperature.

4.2 Posology And Method Of Administration

Oral administration.

Adults and children 12 and over: One single-dose container. The product is taken orally without water.

The dose may be repeated every 4 hours.

No more than four doses should be taken in 24 hours.

Children under 12 years: Not to be given to children under 12 without medical advice.

Elderly: There is no indication that dosage need be modified in the elderly.

4.3 Contraindications

Severe coronary heart disease and cardiovascular disorders. Hypertension. Hyperthyroidism. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors. Hypersensitivity to paracetamol, phenylephrine or any other ingredient.

4.4 Special Warnings And Precautions For Use

Use with caution in patients with Raynaud's phenomenon or diabetes mellitus. Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Patients should be advised not to take other paracetamol-containing products concurrently.

Label warnings: Do not exceed the stated dose. Keep all medicines out of the reach and sight of children. Contains paracetamol (panel). If symptoms persist consult your doctor. If you are pregnant or are being prescribed medicine by your doctor, seek his advice before taking this product.

Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Phenylephrine may adversely interact with other sympathomimetics, vasodilators and β-blockers. Drugs which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdose. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors because of the risk of hypertensive crisis.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy And Lactation

Due to the vasoconstrictive properties of phenylephrine the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh the risk. There is no information on use in lactation.

Epidemiological studies in human pregnancy have shown no ill-effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Paracetamol: Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Phenylephrine hydrochloride: Rarely, high blood pressure with headache, vomiting and palpitations, which are only likely to occur with overdose. Also rare reports of allergic reactions.

4.9 Overdose

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine, which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

Features of severe overdose of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression. Treatment includes early gastric lavage and symptomatic and supportive measures. Hypertensive effects may be treated with an i.v. α-receptor blocking agent.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol: Paracetamol has both analgesic and antipyretic activity which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system.

Phenylephrine: Phenylephrine is a post-synaptic α-receptor agonist with low cardioselective β-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

5.2 Pharmacokinetic Properties

Paracetamol: Paracetamol is absorbed rapidly and completely mainly from the small intestine producing peak plasma levels after 15-20 minutes following oral dosing. The systemic availability is subject to first-pass metabolism and varies with dose between 70% and 90%. The drug is rapidly and widely distributed throughout the body and is eliminated from plasma with a T2 of approximately 2 hours. The major metabolites are glucuronide and sulphate conjugates (>80%) which are excreted in urine.

Phenylephrine: Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethyl cellulose

Ascorbic acid

Glyceryl tristearate

Tartaric acid

Sodium carbonate anhydrous

Aspartame

Lemon flavour

Sweet flavour

Xylitol

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Polyethylene terephthalate/aluminium/polyethylene sachets.

Pack size: 10

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for handling.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham

NG2 3AA

8. Marketing Authorisation Number(S)

PL00014/0634

9. Date Of First Authorisation/Renewal Of The Authorisation

19 July 2002

10. Date Of Revision Of The Text

August 2006

Midazolam Syrup

Generic Name: midazolam hydrochloride
MIDAZOLAM HYDROCHLORIDE SYRUP CIV

10 mg / 5mL

Rx Only

Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants (eg, opioids). Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, THAT CAN PROVIDE FOR CONTINUOUS MONITORING OF RESPIRATORY AND CARDIAC FUNCTION. IMMEDIATE AVAILABILITY OF RESUSCITATIVE DRUGS AND AGE- AND SIZE- APPROPRIATE EQUIPMENT FOR VENTILATION AND INTUBATION, AND PERSONNEL TRAINED IN THEIR USE AND SKILLED IN AIRWAY MANAGEMENT SHOULD BE ASSURED (see WARNINGS). For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Midazolam Syrup Description

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration. Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine hydrochloride. Midazolam hydrochloride has the molecular formula C18H13CIFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula:

Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 - 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6. Above pH 5, at least 99% of the mixture is present in the closed-ring form.

Midazolam Syrup - Clinical Pharmacology

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

Pharmacodynamics

Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the γ-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.

Data from published reports of studies in pediatric patients clearly demonstrate that oral midazolam provides safe and effective sedation and anxiolysis prior to surgical procedures that require anesthesia as well as before other procedures that require sedation but may not require anesthesia. The most commonly reported effective doses range from 0.25 to 1 mg/kg in children (6 months to <16 years). The single most commonly reported effective dose is 0.5 mg/kg. Time to onset of effect is most frequently reported as 10 to 20 minutes.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Following premedication with oral midazolam, time to recovery has been assessed in pediatric patients using various measures, such as time to eye opening, time to extubation, time in the recovery room, and time to discharge from the hospital. Most placebo-controlled trials (8 total) have shown little effect of oral midazolam on recovery time from general anesthesia; however, a number of other placebo-controlled studies (5 total) have demonstrated some prolongation in recovery time following premedication with oral midazolam. Prolonged recovery may be related to duration of the surgical procedure and/or use of other medications with central nervous system depressant properties.

Partial or complete impairment of recall following oral midazolam has been demonstrated in several studies. Amnesia for the surgical experience was greater after oral midazolam when used as a premedicant than after placebo and was generally considered a benefit. In one study, 69% of midazolam patients did not remember mask application versus 6% of placebo patients.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been reported in <1% of pediatric patients following premedication (eg, sedation prior to induction of anesthesia) with midazolam HCl syrup; the potential for such adverse events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease (see WARNINGS).

Concomitant use of barbiturates or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may contribute to profound and/or prolonged drug effect. In one study of pediatric patients undergoing elective repair of congenital cardiac defects, premedication regimens (oral dose of 0.75 mg/kg midazolam or IM morphine plus scopolamine) increased transcutaneous carbon dioxide (PtcCO2), decreased SpO2 (as measured by pulse oximetry), and decreased respiratory rates preferentially in patients with pulmonary hypertension. This suggests that hypercarbia or hypoxia following premedication might pose a risk to children with congenital heart disease and pulmonary hypertension. In a study of an adult population 65 years and older, the preinduction administration of oral midazolam 7.5 mg resulted in a 60% incidence of hypoxemia (paO2<90% for over 30 seconds) at some time during the operative procedure versus 15% for the nonpremedicated group.

Pharmacokinetics

Absorption

Midazolam is rapidly absorbed after oral administration and is subject to substantial intestinal and hepatic first-pass metabolism. The pharmacokinetics of midazolam and its major metabolite, α-hydroxymidazolam, and the absolute bioavailability of midazolam HCl syrup were studied in pediatric patients of different ages (6 months to <16 years old) over a 0.25 to 1 mg/kg dose range. Pharmacokinetic parameters from this study are presented in Table 1. The mean Tmax values across dose groups (0.25, 0.5, and 1 mg/kg) range from 0.17 to 2.65 hours. Midazolam exhibits linear pharmacokinetics between oral doses of 0.25 to 1 mg/kg (up to a maximum dose of 40 mg) across the age groups ranging from 6 months to <16 years. Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. The absolute bioavailability of the Midazolam Syrup in pediatric patients is about 36%, which is not affected by pediatric age or weight. The AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose in pediatric patients is higher than for an IV dose (0.38 to 0.75 versus 0.21 to 0.39 across the age group of 6 months to <16 years), and the AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose is higher in pediatric patients than in adults (0.38 to 0.75 versus 0.40 to 0.56).

Food effect has not been tested using midazolam HCl syrup. When a 15 mg oral tablet of midazolam was administered with food to adults, the absorption and disposition of midazolam was not affected. Feeding is generally contraindicated prior to sedation of pediatric patients for procedures.

Table1. Pharmacokinetics of Midazolam Following Single Dose Administration of Midazolam HCl Syrup

Number of Subjects/age group	Dose (mg/kg)	Tmax (h)	Cmax (ng/mL)	T1/2 (h)	AUC 0-∞ (ng∙h/mL)
6 months to <2 years old
1	0.25	0.17	28.0	5.82	67.6
1	0.50	0.35	66.0	2.22	152
1	1.00	0.17	61.2	2.97	224
2 to <12 years old
18	0.25	0.72 ± 0.44	63.0 ± 30.0	3.16 ± 1.50	138 ± 89.5
18	0.50	0.95 ± 0.53	126 ± 75.8	2.71 ± 1.09	306 ± 196
18	1.00	0.88 ± 0.99	201 ± 101	2.37 ± 0.96	743 ± 642
12 to <16 years old
4	0.25	2.09 ± 1.35	29.1 ± 8.2	6.83 ± 3.84	155 ± 84.6
4	0.50	2.65 ± 1.58	118 ± 81.2	4.35 ± 3.31	821 ± 568
2	1.00	0.55 ± 0.28	191 ± 47.4	2.51 ± 0.18	566 ± 15.7

Distribution

The extent of plasma protein binding of midazolam is moderately high and concentration independent. In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, α-hydroxymidazolam is bound to the extent of 89%. In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg.

Metabolism

Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the α–hydroxyl metabolite which is present in unconjugated and conjugated forms in human plasma. The α- hydroxymidazolam glucuronide is then excreted in urine. In a study in which adult volunteers were administered intravenous midazolam (0.1 mg/kg) and α–hydroxymidazolam (0.15 mg/kg), the pharmacodynamic parameter values of the maximum effect (Emax) and concentration eliciting half-maximal effect (EC50) were similar for both compounds. The effects studied were reaction time and errors in tracing tests. The results indicate that α–hydroxymidazolam is equipotent and equally effective as unchanged midazolam on a total plasma concentration basis. After oral or intravenous administration, 63% to 80% of midazolam is recovered in urine as α–hydroxymidazolam glucuronide. No significant amount of parent drug or metabolites is extractable from urine before beta-glucuronidase and sulfatase deconjugation, indicating that the urinary metabolites are excreted mainly as conjugates.

Midazolam is also metabolized to two other minor metabolites: 4-hydroxy metabolite (about 3% of the dose) and 1,4-dihydroxy metabolite (about 1% of the dose) are excreted in small amounts in the urine as conjugates.

Elimination

The mean elimination half-life of midazolam ranged from 2.2 to 6.8 hours following single oral doses of 0.25, 0.5, and 1 mg/kg of midazolam (midazolam HCl syrup). Similar results (ranged from 2.9 to 4.5 hours) for the mean elimination half-life were observed following IV administration of 0.15 mg/kg of midazolam to pediatric patients (6 months to <16 years old). In the same group of patients receiving the 0.15 mg/kg IV dose, the mean total clearance ranged from 9.3 to 11 mL/min/kg.

Pharmacokinetic-Pharmacodynamic Relationships

The relationship between plasma concentration and sedation and anxiolysis scores of oral Midazolam Syrup (single oral doses of 0.25, 0.5, or 1 mg/kg) was investigated in three age groups of pediatric patients (6 months to <2 years, 2 to <12 years, and 12 to <16 years old). In this study, the patient's sedation scores were recorded at baseline and at 10-minute intervals up to 30 minutes after oral dosing until satisfactory sedation ("drowsy" or "asleep but responsive to mild shaking" or "asleep and not responsive to mild shaking") was achieved. Anxiolysis scores were measured at the time when the patient was separated from his/her parents and at mask induction. The results of the analyses showed that the mean midazolam plasma concentration as well as the mean of midazolam plus α–hydroxymidazolam for those patients with a sedation score of 4 (asleep but responsive to mild shaking) is significantly different than the mean concentrations for those patients with a sedation score of 3 (drowsy), which is significantly different than the mean concentrations for patients with a sedation score of 2 (awake/calm). The statistical analysis indicates that the greater the midazolam, or midazolam plus α–hydroxymidazolam concentration, the greater the maximum sedation score for pediatric patients. No such trend was observed between anxiolysis scores and the mean midazolam concentration or mean of midazolam plus α–hydroxymidazolam concentration; however, anxiolysis is a more variable surrogate measurement of clinical response.

Special Populations

Renal Impairment

Although the pharmacokinetics of intravenous midazolam in adult patients with chronic renal failure differed from those of subjects with normal renal function, there were no alterations in the distribution, elimination, or clearance of unbound drug in the renal failure patients. However, the effects of renal impairment on the active metabolite α–hydroxymidazolam are unknown.

Hepatic Dysfunction

Chronic hepatic disease alters the pharmacokinetics of midazolam. Following oral administration of 15 mg of midazolam, Cmax and bioavailability values were 43% and 100% higher, respectively, in adult patients with hepatic cirrhosis than adult subjects with normal liver function. In the same patients with hepatic cirrhosis, following IV administration of 7.5 mg of midazolam, the clearance of midazolam was reduced by about 40% and the elimination half-life was increased by about 90% compared with subjects with normal liver function. Midazolam should be titrated for the desired effect in patients with chronic hepatic disease.

Congestive Heart Failure

Following oral administration of 7.5 mg of midazolam, elimination half-life values were 43% higher in adult patients with congestive heart failure than in control subjects.

Neonates

Midazolam HCl syrup has not been studied in pediatric patients less than 6 months of age.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

INHIBITORS OF CYP3A4 ISOZYMES

Table 2 summarizes the changes in the Cmax and AUC of midazolam when drugs known to inhibit CYP3A4 were concurrently administered with oral midazolam in adults subjects.

Table 2.

Interacting Drug	Adult Doses Studied	% Increase in Cmax of Oral Midazolam	% Increase in AUC of Oral Midazolam
Cimetidine	800-1200 mg up to qid in divided doses	6-138	10-102
Diltiazem	60 mg tid	105	275
Erythromycin	500 mg tid	170-171	281-341
Fluconazole	200 mg qd	150	250
Grapefruit Juice	200 mL	56	52
Itraconazole	100-200 mg qd	80-240	240-980
Ketoconazole	400 mg qd	309	1490
Ranitidine	150 mg bid or tid;	15-67	9-66
	300 mg qd
Roxithromycin	300 mg qd	37	47
Saquinavir	1200 mg tid	235	514
Verapamil	80 mg tid	97	192

Other drugs known to inhibit the effects of CYP3A4, such as protease inhibitors, would be expected to have similar effects on these midazolam pharmacokinetic parameters.

INDUCERS OF CYP3A4 ISOZYMES

Table 3 summarizes the changes in the Cmax and AUC of midazolam when drugs known to induce CYP3A4 were concurrently administered with oral midazolam in adult subjects. The clinical significance of these changes is unclear.

Table 3.

Interacting Drug	Adult Doses Studied	% Decrease in Cmax of Oral Midazolam	% Decrease in AUC of Oral Midazolam
Carbamazepine	Therapeutic Doses	93	94
Phenytoin	Therapeutic Doses	93	94
Rifampin	600 mg/day	94	96

Although not tested, phenobarbital, rifabutin and other drugs known to induce the effects of CYP3A4 would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Drugs that did not affect midazolam pharmacokinetics are presented in Table 4.

Table 4.

Interacting Drug	Adult Doses Studied
Azithromycin	500 mg/day
Nitrendipine	20 mg
Terbinafine	200 mg/day

Clinical Trials

Dose Ranging, Safety and Efficacy Study With Midazolam HCl Syrup in Pediatric Patients

The effectiveness of midazolam HCl syrup as a premedicant to sedate and calm pediatric patients prior to induction of general anesthesia was compared among three different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II or III were stratified to 1 of 3 age groups (6 months to <2 years, 2 to <6 years, and 6 to <16 years), and within each age group randomized to 1 of 3 dosing groups (0.25, 0.5, and 1 mg/kg up to a maximum dose of 20 mg). Greater than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes posttreatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes after treatment for >70% of patients who started with an unsatisfactory baseline rating. Whereas pairwise comparisons (0.25 mg/kg versus 0.5 mg/kg groups, and 0.5 mg/kg versus 1 mg/kg groups) on satisfactory sedation did not yield significant p-values (p=0.08 in both cases), comparative analysis of the clinical response between the high and low doses demonstrated that a higher proportion of patients in the 1 mg/kg dose group exhibited satisfactory sedation and anxiolysis as compared to the 0.25 mg/kg group (p<0.05).

Indications and Usage for Midazolam Syrup

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use (see WARNINGS).

MIDAZOLAM HCl SYRUP MUST BE USED AS SPECIFIED IN THE LABEL.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY).

Contraindications

Midazolam HCl syrup is contraindicated in patients with a known hypersensitivity to the drug or allergies to formulation excipients. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction of general anesthesia with injectable midazolam; patients with glaucoma have not been studied.

Warnings

Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants. These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest (see box WARNING). When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently (see DOSAGE AND ADMINISTRATION).

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age-and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, that are equipped to provide continuous monitoring of respiratory and cardiac function. Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional. If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because midazolam can depress respiration (see CLINICAL PHARMACOLOGY), especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND ADMINISTRATION), it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. Consideration should be given to the possibility of paradoxical reaction. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Coadministration of oral midazolam in patients who are taking ketoconazole, intraconazole and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to decrease in plasma clearance of midazolam (see PHARMACOKINETICS: Drug-Drug Interactions and PRECAUTIONS). Due to potential for intense and prolonged sedation and respiratory depression, Midazolam Syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered. Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam. Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Patients with chronic renal failure and patients with congestive heart failure eliminate Midazolam more slowly (see CLINICAL PHARMACOLOGY).

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam HCl syrup (see CLINICAL PHARMACOLOGY) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. Particular care should be taken to assure safe ambulation.

Usage in Pregnancy

Although midazolam HCl syrup has not been studied in pregnant patients, an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) have been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Usage in Preterm Infants and Neonates

Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Precautions

Use With Other CNS Depressants

The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects may range from mild sedation to deep levels of sedation with a potential loss of protective reflexes, particularly when coadministered with anesthetic agents or other CNS depressants. Care must be taken to individualize the dose of midazolam based on the patient's age, underlying medical/surgical conditions, concomitant medications, and to have the personnel, age- and size-appropriate equipment and facilities available for monitoring and intervention. Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management.

Use With Inhibitors of CYP3A4 Isozymes

Oral midazolam should be used with caution in patients treated with drugs known to inhibit CYP3A4 because inhibition of metabolism may lead to more intense and prolonged sedation (see PHARMACOKINETICS: Drug-Drug Interactions, and WARNINGS). Patients being treated with medications known to inhibit CYP3A4 isozymes should be treated with lower than recommended doses of midazolam HCl syrup and the clinician should expect a more intense and prolonged effect.

Information for Patients

To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate:

1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.


2. Inform your physician if you are pregnant or are planning to become pregnant.


3. Inform your physician if you are nursing.


4. Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.


5. Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.


6. For pediatric patients, particular care should be taken to assure safe ambulation.

Drug Interactions

Inhibitors of CYP3A4 Isozymes

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the Cmax and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when midazolam HCl syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated (see PHARMACOKINETICS: Drug-Drug Interactions).

Inducers of CYP3A4 Isozymes

Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased Cmax and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

CNS Depressants

One case was reported of inadequate sedation with chloral hydrate and later with oral Midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION).

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Drug/Laboratory Test Interactions

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9, and 80 mg/kg/day. In female mice in the highest dose (10 times the highest oral dose of 1 mg/kg for a pediatric patient, on a mg/m2 basis) group there was a marked increase in the incidence of hepatic tumors. In high-dose (19 times the pediatric dose) male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (1 to 2 times the pediatric dose) did not increase the incidence of tumors in mice or rats. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be single or intermittent doses.

Mutagenesis

Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.

Impairment of Fertility

A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 16 mg/kg/day PO (3 times the human dose of 1 mg/kg, on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category D

(see WARNINGS).

Embryo-fetal development studies, performed with midazolam maleate in mice (at up to 120 mg/kg/day PO, 10 times the human dose of 1 mg/kg on a mg/m2 basis), rats (at up to 4 mg/kg/day IV, 8 times the human IV dose of 5 mg) and rabbits (at up to 100 mg/kg/day PO, 32 times the human oral dose of 1 mg/kg on a mg/m2 basis), did not show evidence of teratogenicity.

Nonteratogenic Effects

Studies in rats showed no adverse effects on reproductive parameters during gestation and lactation. Dosages tested (4 mg/kg IV and 50 mg/kg PO) were approximately 8 times each of the human doses on a mg/m2 basis.

Labor and Delivery

In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug.

The use of midazolam HCl syrup in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, Midazolam Syrup is not recommended for obstetrical use.

Nursing Mothers

Midazolam is excreted in human milk. Caution should be exercised when Midazolam Syrup is administered to a nursing woman.

Geriatric Use

The safety and efficacy of this product have not been fully studied in geriatric patients. Therefore, there are no available data on a safe dosing regimen. One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO2<90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group. Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease

Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects. One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crises that had been triggered by premedication. In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects. Both premedication regimens increased PtcCO2 and decreased SpO2 and respiratory rates preferentially in patients with pulmonary hypertension.

Adverse Reactions

The distribution of adverse events occurring in patients evaluated in a randomized, double-blind, parallel-group trial are presented in Tables 5 and 6 by body system in order of decreasing frequency: for the premedication period (eg, sedation period prior to induction of anesthesia) alone, see Table 5; for over the entire monitoring period including premedication, anesthesia and recovery, see Table 6.

The distribution of adverse events occurring during the premedication period, before induction of anesthesia, is presented in Table 5. Emesis which occurred in 31/397 (8%) patients over the entire monitoring period, occurred in 3/397 (0.8%) of patients during the premedication period (from midazolam administration to mask induction). Nausea, which occurred in 14/397 (4%) patients over the entire monitoring period (premedication, anesthesia and recovery), occurred in 2/397 (0.5%) patients during the premedication period.

This distribution of all adverse events occurring in ≥1% of patients over the entire monitoring period are presented in Table 6. For the entire monitoring period (premedication, anesthesia and recovery), adverse events were reported by 82/397 (21%) patients who received midazolam overall. The most frequently reported adverse events were emesis occurring in 31/397 (8%) patients and nausea occurring in 14/397 (4%) patients. Most of these gastrointestinal events occurred after the administration of other anesthetic agents.

For the respiratory system overall, adverse events (hypoxia, laryngospasm, rhonchi, coughing, respiratory depression, airway obstruction, upper-airway congestion, shallow respirations), occurred during the entire monitoring period in 31/397 (8%) patients and increased in frequency as dosage was increased: 7/132 (5%) patients in the 0.25 mg/kg dose group, 9/132 (7%) patients in the 0.5 mg/kg dose group, and 15/133 (11%) patients in the 1 mg/kg dose group.

Most of the respiratory adverse events occurred during induction, general anesthesia or recovery. One patient (0.25%) experienced a respiratory system adverse event (laryngospasm) during the premedication period. This adverse event occurred precisely at the time of induction. Although many of the respiratory complications occurred in settings of mupper airway procedures or concurrently administered opioids, a number of these events occurred outside of these settings as well. In this study, administration of midazolam HCl syrup was generally accompanied by a slight decrease in both systolic and diastolic blood pressures, as well as a slight increase in heart rate.

Table 5. Adverse Events Occurring During the Premedication Period Before Mask Induction in the Randomized, Double-Blind, Parallel-Group Trial

Body System	Treatment Regimen			Overall
No. Patients with Adverse Events	0.25 mg/kg (n=132) No. (%)	0.5 mg/kg (n=132) No. (%)	1 mg/kg (n=133) No. (%)	(n=397)   No. (%)
* This adverse event occurred precisely at the time of induction.
Gastrointestinal System Disorders
Emesis	1 (0.76%)	1 (0.76%)	1 (0.75%)	3 (0.76%)
Nausea			2 (1.5%)	2 (0.50%)
Respiratory System Disorders

Zomestine 10 mg prolonged-release tablets

1. Name Of The Medicinal Product

Zomestine 10 mg prolonged-release tablets

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains 10 mg oxycodone hydrochloride equivalent to 9.0 mg oxycodone.

Excipient:

The prolonged-release tablets contain a maximum of 30 mg sucrose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablet.

Pink, oblong, biconvex, tablets with break scores on both sides. The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Severe pain, which can be adequately managed only with opioid analgesics.

4.2 Posology And Method Of Administration

The dosage depends on the intensity of pain and the patient's individual susceptibility to the treatment. For doses not realisable/practicable with this medicinal product, other strengths and medicinal products are available.

The following general dosage recommendations apply:

Adults and adolescents (> 12 years)

Dose titration and adjustment

In general, the initial dose for opioid naïve patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of adverse reactions.

Patients already receiving opioids may start treatment with higher dosages taking into account their experience with former opioid therapies.

According to well-controlled clinical studies 10-13 mg oxycodone hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.

Because of individual differences in sensitivity for different opioids, it is recommended that patients should start conservatively with Zomestine prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take Zomestine prolonged-release tablets following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Zomestine prolonged-release tablets are not indicated for the treatment of acute pain and/or breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of Zomestine prolonged-release tablets. Use of the rescue medication more than twice daily indicates that the dose of Zomestine prolonged-release tablets needs to be increased.

The dose should not be adjusted more often than once every 1-2 days until a stable twice daily administration has been achieved.

Following a dose increase from 10 mg to 20 mg taken every 12 hours dose adjustments should be made in steps of approximately one third of the daily dose. The aim is a patient specific dosage which, with twice daily administration, allows for adequate analgesia with tolerable undesirable effects and as little rescue medication as possible as long as pain therapy is needed.

Even distribution (the same dose mornings and evenings) following a fixed schedule (every 12 hours) is appropriate for the majority of the patients. For some patients it may be advantageous to distribute the doses unevenly. In general, the lowest effective analgesic dose should be chosen. For the treatment of non malignant pain a daily dose of 40 mg is generally sufficient; but higher dosages may be necessary. Patients with cancer-related pain may require dosages of 80 to 120 mg, which in individual cases can be increased to up to 400 mg. If even higher doses are required, the dose should be decided individually balancing efficacy with the tolerance and risk of undesirable effects.

Method of administration

For oral use.

Zomestine prolonged-release tablets should be taken twice daily based on a fixed schedule at the dosage determined.

The prolonged-release tablets may be taken with or independent of meals with a sufficient amount of liquid. Zomestine prolonged-release tablets must be swallowed whole, not chewed.

Zomestine prolonged-release tablets should not be used with alcoholic beverages.

Duration of administration

Zomestine should not be taken longer than necessary. If long-term treatment is necessary due to the type and severity of the illness careful and regular monitoring is required to determine whether and to what extent treatment should be continued. If opioid therapy is no longer indicated it may be advisable to reduce the daily dose gradually in order to prevent symptoms of a withdrawal syndrome.

Children under 12 years of age

Zomestine prolonged-release tablets are not recommended for children under 12 years of age.

Elderly patients

Elderly patients without clinical manifestation of impaired liver and/or kidney function usually do not require dose adjustments.

Risk patients

Risk patients, for example patients with impaired renal or hepatic function, low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naïve. Therefore the lowest recommended dosage, i.e. 10 mg, may not be suitable as a starting dose. Dose titration should be performed in accordance with the individual clinical situation.

4.3 Contraindications

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

• severe respiratory depression with hypoxia and/or hypercapnia

• severe chronic obstructive pulmonary disease

• Cor pulmonale

• severe bronchial asthma

• Paralytic ileus

• acute abdomen, delayed gastric emptying.

4.4 Special Warnings And Precautions For Use

Zomestine prolonged-release tablets have not been studied in children younger than 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.

Caution is required in elderly or debilitated patients, in patients with severe impairment of lung, liver or kidney function, myxoedema, hypothyroidism, Addison's disease (adrenal insufficiency), intoxication psychosis (e.g. alcohol), prostatic hypertrophy, alcoholism, known opioid dependence, delirium tremens, pancreatitis, diseases of the biliary tract, biliary or ureteric colic, conditions with increased brain pressure, disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking MAO inhibitors.

Special care should be taken when oxycodone is applied in patients undergoing bowel-surgery. Opioids should only be administered post-operatively when the bowel function has been restored.

Patients with severe hepatic impairment should be closely monitored.

Respiratory depression is the most significant risk induced by opioids and is most likely to occur in elderly or debilitated patients. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. In predisposed patients opioids can cause severe decrease in blood pressure.

Long-term use of Zomestine prolonged-release tablets can cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. There is a cross-tolerance to other opioids. Chronic use of Zomestine prolonged-release tablets can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy. If therapy with oxycodone is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.

Zomestine prolonged-release tablets have a primary dependence potential. However, when used as directed in patients with chronic pain the risk of developing physical or psychological dependence is markedly reduced or needs to be assessed in a differentiated manner. There are no data available on the actual incidence of psychological dependence in chronic pain patients. In patients with a history of alcohol and drug abuse the medicinal product must be prescribed with special care.

The safety of Zomestine prolonged-release tablets used pre-operatively has not been established and cannot be recommended.

In case of abusive parenteral venous injection the tablet excipients may lead to necrosis of the local tissue, granulomas of the lung or other serious, potentially fatal events. To avoid damage to the controlled release properties of the tablets the prolonged-release tablets must not be chewed or crushed. The administration of chewed or crushed tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Zomestine prolonged-release tablets must not be taken with alcoholic beverages, since this might result in an increased incidence of undesirable effects (e.g. somnolence, respiratory depression).

Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.

Use of Zomestine as a doping agent may become a health hazard.

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Central nervous system depressants (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants, antihistamines, antiemetics) and other opioids or alcohol can enhance the adverse reactions of oxycodone, in particular respiratory depression.

Anticholinergics (e.g. neuroleptics, antihistamines, antiemetics, antiparkinson medicinal products) can enhance the anticholinergic undesirable effects of oxycodone (such as constipation, dry mouth or micturition disorders).

Cimetidine can inhibit the metabolism of oxycodone.

MAO inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper- or hypotensive crisis (see section 4.4).

The inhibition of cytochrome P450 2D6 and 3A4 has no clinical relevance, however, strong CYP2D6 inhibitors may have an effect on the elimination of oxycodone. The effect of other relevant isoenzyme inhibitors on the metabolism of oxycodone is not known. Potential interactions should be taken into account.

Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with Zomestine prolonged-release tablets.

There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other active substances.

4.6 Pregnancy And Lactation

Pregnancy

Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. Oxycodone crosses the placenta. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects.

Prolonged use of oxycodone during pregnancy can cause withdrawal symptoms in newborns. Use of oxycodone during labour can cause foetal respiratory depression. Oxycodone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Lactation

Zomestine prolonged-release tablets should not be taken during lactation (see section 4.3).

Oxycodone passes into breast milk. The milk/plasma concentration ratio was 3.4:1 and oxycodone effects in the suckling infant are therefore conceivable. A risk to the suckling child cannot be excluded in particular following intake of multiple doses of oxycodone by the breast-feeding mother. Breast-feeding should be discontinued during treatment with oxycodone.

4.7 Effects On Ability To Drive And Use Machines

Oxycodone can impair alertness and reactivity to such an extent that the ability to drive and operate machinery is affected or ceases altogether. With stable therapy, a general ban on driving a vehicle is not necessary. The treating physician must assess the individual situation.

4.8 Undesirable Effects

Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex.

The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. Frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

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

Blood and lymphatic system disorders

Rare: lymphadenopathy

Endocrine disorders

Uncommon: syndrome of inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Common: anorexia

Rare: dehydration

Psychiatric disorders

Common: various psychological adverse reactions including changes in mood (e.g. anxiety, depression, euphoria), changes in activity (mostly supression sometimes associated with lethargy, occasionally increase with agitation, nervousness and insomnia) and changes in cognitive performance (abnormal thinking, confusion, amnesia, isolated cases of speech disorders)

Uncommon: change in perception such as depersonalisation, hallucinations, change in taste, visual disturbances, hyperacousis

Nervous system disorders

Very common: somnolence, dizziness, headache

Common: asthenia, paraesthesia

Uncommon: both increased and decreased muscle tone, tremor, involuntary muscle contractions, hypaesthesia, coordination disturbances, malaise, vertigo

Rare: seizures, in particular in epileptic patients or patients with tendency to convulsions, muscle spasm

Eye disorders

Uncommon: lacrimation disorder, miosis

Cardiac and vascular disorders

Common: lowering of blood pressure, rarely accompanied by secondary symptoms such as palpitations, syncope, bronchospasm

Uncommon: supraventricular tachycardia, vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: respiratory depression

Uncommon: increased coughing, pharyngitis, rhinitis, voice changes

Gastrointestinal disorders

Very common: constipation, nausea, vomiting

Common: dry mouth, rarely accompanied by thirst and difficulty swallowing; gastrointestinal disorders such as abdominal pain, diarrhoea, eructation, dyspepsia, loss of appetite

Uncommon: biliary colics, oral ulcers, gingivitis, stomatitis, flatulence

Rare: gum bleeding, increased appetite, tarry stool, tooth staining and damage, ileus

Skin and subcutaneous tissue disorders

Very common: itching

Common: skin eruptions including rash, in rare cases increased photosensitivity, in isolated cases urticaria or exfoliative dermatitis

Rare: dry skin, herpes simplex

Renal and urinary disorders

Common: micturition disturbances (urinary retention, but also increased urge to urinate)

Rare: haematuria

Reproductive system and breast disorders

Uncommon: reduced libido, impotence

Rare: amenorrhoea

General disorders and administration site conditions

Common: sweating and even chills

Uncommon: accidental injuries, pain (e.g. chest pain), oedema, migraine, physical dependence with withdrawal symptoms, allergic reactions

Rare: weight changes (increase or decrease), cellulitis

Very rare: anaphylactic reactions

Tolerance and dependence may develop.

4.9 Overdose

Symptoms of overdose

Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

Therapy of overdose

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation

In the event of overdosing intravenous administration of an opiate antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient. Gastric lavage can be taken into consideration. Consider activated charcoal (50 g for adults, 10 -15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged-release preparations; however there is no evidence to support this.

For speeding up the passage a suitable laxative (e.g. a PEG based solution) may be useful.

Supportive measures (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. If necessary, assisted ventilation as well as maintenance of water and electrolyte balance.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Natural opium alkaloids, ATC-Code: N02AA05

Oxycodone shows an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord. It acts at these receptors as an opioid agonist without an antagonistic effect. The therapeutic effect is mainly analgesic and sedative. Compared to rapid- release oxycodone, given alone or in combination with other substances, the prolonged-release tablets provide pain relief for a markedly longer period without increased occurrence of undesirable effects.

5.2 Pharmacokinetic Properties

Absorption

The relative bioavailability of Zomestine prolonged-release tablets is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3 hours after intake of the prolonged-release tablets compared to 1 to 1.5 hours. Peak plasma concentrations and oscillations of the concentrations of oxycodone from the prolonged-release and rapid-release formulations are comparable when given at the same daily dose at intervals of 12 and 6 hours, respectively.

A fat-rich meal before the intake of the tablets does not affect the maximum concentration or the extent of absorption of oxycodone.

The tablets must not be crushed or chewed as this leads to rapid oxycodone release due to the damage of the prolonged-release properties.

Distribution

The absolute bioavailability of oxycodone is approximately two thirds relative to parenteral administration. In steady state, the volume of distribution of oxycodone amounts to 2.6 l/kg; plasma protein binding to 38-45%; the elimination half-life to 4 to 6 hours and plasma clearance to 0.8 l/min. The elimination half-life of oxycodone from prolonged-release tablets is 4-5 hours with steady state values being achieved after a mean of 1 day.

Metabolism

Oxycodone is metabolised in the intestine and liver via the P450 cytochrome system to noroxycodone and oxymorphone as well as to several glucuronide conjugates. In vitro studies suggest that therapeutic doses of cimetidine probably have no relevant effect on the formation of noroxycodone. In man, quinidine reduces the production of oxymorphone while the pharmacodynamic properties of oxycodone remain largely unaffected. The contribution of the metabolites to the overall pharmacodynamic effect is irrelevant.

Elimination

Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.

Linearity/non-linearity

The 5, 10, 20, 40 and 80 mg prolonged-release tablets are bioequivalent in a dose proportional manner with regard to the amount of active substance absorbed as well as comparable with regard to the rate of absorption.

5.3 Preclinical Safety Data

Oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices.

Long-term carcinogenicity studies were not performed.

Oxycodone shows a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of oxycodone to humans at therapeutic concentrations may be ruled out with adequate certainty.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:Sugar spheres (sucrose, maize starch)

Hypromellose

Talc

Ethylcellulose

Hyprolose

Propylene glycol

Carmellose sodium

Microcrystalline cellulose

Magnesium stearate

Colloidal anhydrous silica

Tablet coating:

Titanium dioxide (E171)

Hypromellose

Macrogol 6000

Talc

Red iron oxide (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 year

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Child resistant PVC/PE/PVDC-aluminium blisters consisting of a white opaque PVC/PE/PVDC laminated foil and an aluminium foil.

HDPE bottles with child-resistant PP twist-off caps.

Pack sizes:

10, 14, 20, 28, 30, 50, 56, 98, 100 prolonged-release tablets in blister.

10, 20, 30, 50, 100 prolonged-release tablets in HDPE bottles.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Accord Healthcare Limited,

Sage house, 319 Pinner road,

North Harrow, Middlesex, HA1 4HF

United Kingdom

8. Marketing Authorisation Number(S)

PL20075/0327

9. Date Of First Authorisation/Renewal Of The Authorisation

21/09/2011

10. Date Of Revision Of The Text

21/09/2011

Finasteride 5mg Tablets

1. Name Of The Medicinal Product

Finasteride 5mg film-coated tablets

2. Qualitative And Quantitative Composition

One film-coated tablet contains 5mg finasteride

Excipient: lactose monohydrate (97.5mg)

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

Blue coloured, circular, biconvex, beveled edged film-coated tablets debossed with 'E' on one side and '61' on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Finasteride 5mg is indicated for the treatment and control of benign prostatic hyperplasia (BPH) to:

- cause regression of the enlarged prostate, improve urinary flow and improve the symptoms associated with BPH

- reduce the incidence of acute urinary retention and reduce need for surgery including transurethral resection of the prostate (TURP) and prostatectomy

Finasteride should be administered in patients with an enlarged prostate (prostate volume above ca. 40ml).

4.2 Posology And Method Of Administration

Finasteride is for oral use only.

Dosage in adults

The recommended dosage is one 5mg tablet daily with or without food. The tablet should be swallowed whole and must not be divided or crushed (see section 6.6).

Even though improvement can be seen within a short time, treatment for at least 6 months may be necessary in order to determine objectively whether a satisfactory response to treatment has been achieved.

Dosage in the elderly

Dosage adjustments are not necessary although pharmacokinetic studies have shown that the elimination rate of finasteride is slightly decreased in patients over the age of 70.

Dosage in hepatic insufficiency

There is no data available in patients with hepatic insufficiency (see section 4.4).

Dosage in renal insufficiency

Dosage adjustments are not necessary in patients with varying degrees of renal insufficiency (starting from creatinine clearance as low as 9ml/min) as in pharmacokinetic studies renal insufficiency was not found to affect the elimination of finasteride. Finasteride has not been studied in patients on haemodialysis.

4.3 Contraindications

Finasteride is not indicated for use in women or children.

Finasteride is contraindicated in the following:

• Hypersensitivity to any component of this product.

• Pregnancy–Use in women when they are or may potentially be pregnant (see 4.6 Pregnancy and lactation, Exposure to finasteride – risk to male fetus).

4.4 Special Warnings And Precautions For Use

General:

To avoid obstructive complications it is important that patients with large residual urine and/or heavily decreased urinary flow are carefully controlled. The possibility of surgery should be an option.

Effects on prostate-specific antigen (PSA) and prostate cancer detection:

No clinical benefit has yet been demonstrated in patients with prostate cancer treated with finasteride. Patients with BPH and elevated serum prostate specific antigen (PSA) were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these BPH studies, finasteride did not appear to alter the rate of prostate cancer detection, and the overall incidence of prostate cancer was not statistically different in patients treated with finasteride or placebo.

Digital rectal examinations as well as other evaluations for prostate cancer are recommended prior to initiating therapy with finasteride and periodically thereafter. Serum PSA is also used for prostate cancer detection. Generally a baseline PSA > 10 ng/ml (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 ng/ml, further evaluation is advisable. There is considerable overlap in PSA levels among men with and without prostate cancer. Therefore, in men with BPH, PSA values within the normal refrence range do not rule out prostate cancer, regardless of treatment with finasteride. A baseline PSA < 4 ng/ml does not exclude prostate cancer.

Finasteride causes a decrease in serum PSA concentrations by approximately 50% in patients with BPH, even in the presence of prostate cancer. This decrease in serum PSA levels in patients with BPH treated with finasteride should be considered when evaluating PSA data and does not rule out concomitant prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3000 patients in the 4- year, double-blind, placebo-controlled finasteride Long-Term Efficacy and Safety Study [PLESS] confirmed that in typical patients treated with finasteride for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.

Any sustained increase in PSA levels of patients treated with finasteride should be carefully evaluated, including consideration of non-compliance to finasteride therapy.

Percent free PSA (free to total PSA ratio) is not significantly decreased by finasteride. The ratio of free to total PSA remains constant even under the influence of finasteride. When percent free PSA is used as an aid in the detection of prostate cancer, no adjustment to its value is necessary.

Drug/laboratory test interactions

Effect on levels of PSA

Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels decrease in patients treated with finasteride. In most patients, a rapid decrease in PSA is seen within the first months of therapy, after which time PSA levels stabilize to a new baseline. The post-treatment baseline approximates half of the pre-treatment value. Therefore, in typical patients treated with finasteride for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men. For clinical interpretation, see 4.4 Special Warnings and precautions for use, Effects on PSA and prostate cancer detection.

Breast cancer in men

Breast cancer has been reported in men taking finasteride 5 mg during clinical trials and in the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.

Pediatric use

Finasteride is not indicated for use in children.

Safety and effectiveness in children have not been established.

Lactose

The tablet contains lactose monohydrate. Patients with any of the following genetic deficiencies should not take this drug: galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Hepatic insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No drug interactions of clinical importance have been identified. Finasteride is metabolized primarily via, but does not appear to affect significantly, the cytochrome P450 3A4 system. Although the risk for finasteride to affect the pharmacokinetics of other drugs is estimated to be small, it is probable that inhibitors and inducers of cytochrome P450 3A4 will affect the plasma concentration of finasteride. However, based on established safety margins, any increase due to concomitant use of such inhibitors is unlikely to be of clinical significance. Finasteride does not appear to affect significantly the cytochrome P450-linked drug metabolizing enzyme system. Compounds which have been tested in man have included propanolol, digoxin, glibenclamide, warfarin, theophylline and phenazone and no meaningful interactions were found.

4.6 Pregnancy And Lactation

Pregnancy

Finasteride is contraindicated for use in women when they are or may potentially be pregnant (see section 4.3).

Because of the ability of the type II 5α-reductase-inhibitors to inhibit conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male fetus when administered to a pregnant woman (see section 5.3).

Exposure to finasteride - risk to male fetus.

Women should not handle crushed or broken tablets of finasteride when they are or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus (see section 6.6). Finasteride tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed.

Small amounts of finasteride have been recovered from the semen in subjects receiving finasteride 5 mg/day. It is not known whether a male fetus may be adversely affected if his mother is exposed to the semen of a patient being treated with finasteride. When the patient's sexual partner is or may potentially be pregnant, the patient is recommended to minimise exposure of his partner to semen.

Lactation:

Finasteride is not indicated for use in women.

It is not known whether finasteride is excreted in human milk.

4.7 Effects On Ability To Drive And Use Machines

There are no data to suggest that finasteride affects the ability to drive or use machines.

4.8 Undesirable Effects

The most frequent adverse reactions are impotence and decreased libido. These adverse reactions occur early in the course of therapy and resolve with continued treatment in the majority of patients.

The adverse reactions reported during clinical trials and/or post-marketing use are listed in the table below.

Frequency of adverse reactions is determined as follows:

Very common (

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports.

System Organ Class	Frequency: adverse reactions
Investigations	Common: decreased volume of ejaculate
Immune system disorders	Unknown: hypersensitivity reactions including swelling of the lips and face
Cardiac disorders	Unknown: palpitation
Hepatobiliary disorders	Unknown: increased hepatic enzymes
Skin and subcutaneous tissue disorders	Uncommon: rash Unknown: pruritus, urticaria
Reproductive system and breast disorders	Common: impotence, decreased libido Uncommon: ejaculation disorder, breast tenderness, breast enlargement Unknown: testicular pain

In addition following has been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).

Medical therapy of prostatic symptoms (MTOPS):

The MTOPS study compared finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), combination therapy of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), and placebo (n=737). In this study, the safety and tolerability profile of the combination therapy was generally consistent with the profiles of the individual components. The incidence of ejaculation disorder in patients receiving combination therapy was comparable to the sum of incidences of this adverse experience for the two monotherapies.

Other long-term data

In a 7 year placebo-controlled trial that enrolled 18,882 healthy men, of 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving finasteride and 1147 (24.4%) men receiving placebo. In the finasteride group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs 237 (5.1%) men in the placebo group. Additional analyses suggest that the increase in the prevalence of high-grade prostate cancer observed in the finasteride group may be explained by a detection bias due to the effect of finasteride on prostate volume. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (clinical stage T1 or T2) at diagnosis. The clinical significance of the Gleason 7-10 data is unknown.

Laboratory test findings

When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels are decreased in patients treated with finasteride (see section 4.4).

4.9 Overdose

Patients have received single doses of finasteride up to 400mg and multiple doses up to 80mg/day without adverse effects. There is no specific recommended treatment of overdose of finasteride.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Testosterone 5α-reductase inhibitors

ATC code: G04CB01

Finasteride is a synthetic 4-azasteroid, a specific competitive inhibitor of the intracellular enzyme Type-II-5α-reductase. The enzyme converts testosterone into the more potent androgen dihydrotestosterone (DHT). The prostate gland and, consequently, also the hyperplasic prostate tissue are dependent on the conversion of testosterone to DHT for their normal function and growth. Finasteride has no affinity for the androgen receptor.

Clinical studies show a rapid reduction of the serum DHT levels of 70%, which leads to a reduction on prostate volume. After 3 months, a reduction of approx. 20% in the volume of the gland occurs, and the shrinking continues and reaches approximately 27% after 3 years. Marked reduction takes place in the periurethral zone immediately surrounding the urethra. Urodynamic measurements have also confirmed a significant reduction of detrusor pressure as a result of the reduced obstruction.

Significant improvements in maximum urinary flow rate and symptoms have been obtained after a few weeks, compared with the start of treatment. Differences from placebo have been documented at 4 and 7 months, respectively.

All efficacy parameters have been maintained over a 3-year follow-up period.

Effects of four years treatment with finasteride on incidence of acute urine retention need for surgery, symptom-score and prostate volume:

In clinical studies of patients with moderate to severe symptoms of BPH, an enlarged prostate on digital rectal examination and low residual urinary volumes, finasteride reduced the incidence of acute retention of urine from 7/100 to 3/100 over four years and the need for surgery (TURP or prostatectomy) from 10/100 to 5/100. These reductions were associated with a 2-point improvement in QUASI-AUA symptom score (range 0-34), a sustained regression in prostate volume of approximately 20% and a sustained increase in urinary flow rate.

Medical therapy of prostatic symptoms

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a 4- to 6-year study in 3047 men with symptomatic BPH who were randomised to receive finasteride 5mg/day, doxazosin 4 or 8mg/day*, the combination of finasteride 5mg/day and doxazosin 4 or 8mg/day*, or placebo. The primary endpoint was time to clinical progression of BPH, defined as a

* Titrated from 1mg to 4 or 8mg as tolerated over a 3-week period

In this study the safety and tolerability profile of combined treatment was broadly similar to the profile of each of the drugs taken separately. However, undesirable effects concerning the "nervous system" and "uro-genital system" organ classes were observed more frequently when the two drugs were used in combination (see section 4.8).

5.2 Pharmacokinetic Properties

Absorption:

The bioavailability of finasteride is approx. 80%. Peak plasma concentrations are reached approx. 2 hours after drug intake, and absorption is complete after 6-8 hours.

Distribution:

Binding to plasma proteins is approx. 93%. Clearance and volume of distribution are approx. 165ml/min (70-279ml/min) and 76 l (44-96 l), respectively. Accumulation of small amounts of finasteride is seen on repeated administration. After a daily dose of 5mg the lowest steady-state concentration of finasteride has been calculated to be 8-10ng/ml, which remains stable over time.

Biotransformation:

Finasteride is metabolised in the liver. Finasteride does not significantly affect the cytochrome P 450 enzyme system. Two metabolites with low 5α-reductase-inhibiting effects have been identified.

Elimination:

The plasma half-life averages 6 hours (4-12 hours) (in men >70 years of age, 8 hours, range 6-15 hours).

After administration of radioactively labelled finasteride, approx. 39% (32-46%) of the given dose is excreted in the urine in the form of metabolites. Virtually no unchanged finasteride is recovered in the urine. Approximately 57% (51-64%) of the total dose is excreted in the faeces.

Finasteride has been found to cross the blood-brain barrier. Small amounts of finasteride have been recovered in the seminal fluid of treated. In 2 studies of healthy subjects (n=69) receiving finasteride 5mg/day for 6-24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1ng/ml) to 10.54ng/ml. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride 5mg/day ranged from undetectable (<1.0ng/ml) to 21ng/ml. Thus, based on a 5-ml ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5μg) that had no effect on circulating DHT levels in men (see also section 5.3.).

In patients with chronic renal impairment, whose creatinine clearance ranged from 9-55ml/min, the disposition of a single dose of ¹⁴C-finasteride was not different from that in healthy volunteers (see section 4.2). Protein binding also did not differ in patients with renal impairment. A portion of the metabolites which normally is excreted renally was excreted in the faeces. It therefore appears that faecal excretion increases commensurate to the decrease in urinary excretion of metabolites. Dosage adjustment in non-dialysed patients with renal impairment is not necessary.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicology studies in male rats have demonstrated reduced prostate and seminal vesicular weights, reduced secretion from accessory genital glands and reduced fertility index (caused by the primary pharmacological effect of finasteride). The clinical relevance of these findings is unclear.

As with other 5α-reductase inhibitors, feminisation of male rat foetuses has been seen with administration of finasteride in the gestation period. Intravenous administration of finasteride to pregnant rhesus monkeys at doses up to 800ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This dose is about 60-120 times higher than the estimated amount in semen of a man who have taken 5mg finasteride, and to which a woman could be exposed via semen. The reproductive toxicity is believed to be mediated via the intended inhibition of 5α-reductase. Taken into account the species enzyme difference in sensitivity to finasteride inhibition the margin of pharmacological exposure would be about 4 times. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of finasteride 2mg/kg/day (the systemic exposure (AUC) of monkeys was below or in the range of that of men who have taken 5mg finasteride, or approximately 1-2 million times the estimated mount of finasteride in semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no finasteride-related abnormalities were observed in female foetuses at any dose.”

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Lactose monohydrate

Cellulose, microcrystalline

Sodium starch glycolate (Type A)

Starch pregelatinised (maize)

Docusate sodium

Magnesium stearate

Film-coating:

Hydroxypropyl cellulose

Hypromellose

Titanium dioxide

Talc

Indigo carmine aluminium lake (E132)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

PVC/PE/PVDC/Aluminium blister

Pack sizes: 10, 14, 15, 20, 28, 30, 45, 50, 60, 90, 98, 100 or 120 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Women who are pregnant or may become pregnant must not handle crushed or broken Finasteride tablets because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus. Finasteride tablets have a film coating, which prevents contact with the active ingredient provided that the tablets have not been broken or crushed.

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

7. Marketing Authorisation Holder

Aurobindo Pharma Limited,

Ares, Odyssey Business Park,

West End Road, South Ruislip HA4 6QD,

United Kingdom.

tel: ++ 44 20 8845 8811

fax: ++ 44 20 8845 8795

8. Marketing Authorisation Number(S)

PL 20532/0097

9. Date Of First Authorisation/Renewal Of The Authorisation

18/04/2008

10. Date Of Revision Of The Text

04/02/2011