Aciclovir 25 mg / ml Sterile Concentrate

1. Name Of The Medicinal Product

Aciclovir 25 mg/ml Sterile Concentrate

2. Qualitative And Quantitative Composition

Each ml contains 25 mg aciclovir as aciclovir sodium.

Each vial of 10 ml of solution contains 250 mg aciclovir (sodium salt formed in situ)

Each vial of 20 ml of solution contains 500 mg aciclovir (sodium salt formed in situ)

Each vial of 40 ml of solution contains 1 g aciclovir (sodium salt formed in situ)

For excipients, see 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the treatment of severe initial genital herpes in the immunocompromised and the non-immunocompromised.

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the prophylaxis and treatment of Herpes simplex infections in immunocompromised patients.

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the treatment of shingles (Varicella zoster virus) in immunocompetent patients in whom a serious course of the illness can be anticipated.

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the treatment of initial and recurrent Varicella zoster infections in immunocompromised patients.

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the treatment of herpes encephalitis.

Aciclovir 25 mg/ml Sterile Concentrate is indicated for the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.

4.2 Posology And Method Of Administration

Treatment should be started as early as possible during the course of an active infection.

A course of treatment with Aciclovir 25 mg/ml Sterile Concentrate usually lasts between 5 and 7 days, but the duration of treatment may be adjusted according to the patient's condition and response to therapy. Treatment for herpes encephalitis and neonatal Herpes simplex infections usually lasts for at least 10 days.

The duration of prophylactic administration of Aciclovir 25 mg/ml Sterile Concentrate is determined by the duration of the period of risk.

Dosage in adults: Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections (with normal immune response) should be given Aciclovir 25 mg/ml Sterile Concentrate in doses of 5 mg/kg bodyweight every 8 hours.

Immunocompromised patients with Varicella zoster infections or patients with herpes encephalitis should be given Aciclovir 25 mg/ml Sterile Concentrate in doses of 10 mg/kg bodyweight every 8 hours provided renal function is not impaired (see dosage in renal impairment).

The dosage of Aciclovir 25 mg/ml Sterile Concentrate in neonates and infants up to 3 months of age is calculated on the basis of bodyweight.

Neonates and infants up to 3 months of age with Herpes simplex infections should be given Aciclovir 25 mg/ml Sterile Concentrate in doses of 10 mg/kg bodyweight every 8 hours. Treatment for neonatal Herpes simplex infections usually lasts 10 days.

Dosage in Children: The dose of Aciclovir 25 mg/ml Sterile Concentrate for children aged between 3 months and 12 years is calculated on the basis of body surface area.

Children with Herpes simplex (except herpes encephalitis) or Varicella zoster infections (with normal immune response) should be given Aciclovir 25 mg/ml Sterile Concentrate in doses of 250 mg per square metre of body surface area every 8 hours.

In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, Aciclovir 25 mg/ml Sterile Concentrate should be given in doses of 500 mg per square metre body surface area every 8 hours if renal function is not impaired.

Children with impaired renal function require an appropriately modified dose, according to the degree of impairment.

Dosage in the elderly: In the elderly, total aciclovir body clearance declines in parallel with creatinine clearance. Special attention should be given to dosage reduction in elderly patients with impaired creatinine clearance. It is recommended that the state of hydration and the creatinine clearance should be evaluated before the administration of high dosages of aciclovir, especially in elderly patients, who may have reduced renal function despite a normal serum creatinine concentration.

Dosage in renal impairment: Caution is advised when administering Aciclovir 25 mg/ml Sterile Concentrate to patients with impaired renal function since the drug is excreted through the kidneys. The following adjustments in dosage are suggested:

Creatinine Clearance Dosage

25 to 50 ml/min	The dose recommended above (5 or 10 mg/kg bodyweight or 250-500 mg/m2 in children) should be given every 12 hours.
10 to 25 ml/min	The dose recommended above (5 or 10 mg/kg bodyweight or 250-500 mg/m2 in children) should be given every 24 hours.
0 (anuric) to 10 ml/min	In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the dose recommended above (5 or 10 mg/kg bodyweight or 250-500 mg/m2 in children) should be halved and administered every 24 hours. In patients receiving haemodialysis half the dose recommended above should be administered immediately after dialysis and thereafter every 24 hours.

Administration

The required dose of Aciclovir 25 mg/ml Sterile Concentrate should be administered by slow intravenous infusion over a one-hour period and adequate hydration should be established.

Aciclovir 25 mg/ml Sterile Concentrate may be administered by a controlled-rate infusion pump.

Refer to Section 6.6 for instructions on use, preparation and handling.

4.3 Contraindications

Aciclovir 25 mg/ml Sterile Concentrate is contraindicated in patients known to be previously hypersensitive to aciclovir and valaciclovir.

4.4 Special Warnings And Precautions For Use

Solutions of aciclovir are alkaline (pH of approximately 11) and intended for intravenous infusion only and should not be used by any other route.

The dose of Aciclovir 25 mg/ml Sterile Concentrate must be adjusted in patients with impaired renal function in order to avoid accumulation of aciclovir in the body. Infusions of aciclovir must be given over a period of at least one hour in order to avoid renal tubular damage (see dosage in renal impairment).

Although the aqueous solubility of aciclovir exceeds 100 mg/ml, precipitation of aciclovir crystals in renal tubules and the consequent renal tubular damage can occur if the maximum solubility of free aciclovir (2.5 mg/ml at 37°C in water) is exceeded. Aciclovir infusions must be accompanied by adequate hydration. Since maximum urine concentration occurs within the first few hours following infusion particular attention should be given to establish sufficient urine flow during that period. Concomitant use of other nephrotoxic drugs, pre-existing renal disease and dehydration increase the risk of further renal impairment by aciclovir.

In patients receiving Aciclovir 25 mg/ml Sterile Concentrate at higher doses (e.g. for herpes encephalitis), specific care regarding renal function should be taken, particularly when patients are dehydrated or have any renal impairment.

Contact with eyes or unprotected skin should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There have been rare reports of Probenecid, cimetidine, theophylline and mycophenolate mofetil linked to increases in the aciclovir mean half-life and area under the plasma concentration-time curve. In these cases an adjustment of the aciclovir dosage is not thought to be necessary given the large therapeutic range of aciclovir.

According to one case report, co-administration of intravenous aciclovir and lithium caused a four-fold increase in lithium serum concentrations. Lithium concentrations should be closely monitored and a reduced lithium dose may be needed.

When aciclovir is administered concomitantly with theophylline, close monitoring of theophylline concentrations and possible theophylline dose reduction is recommended. A study has shown that when theophylline was given as single 320 mg doses before and with the sixth dose of aciclovir 800 mg five times daily for 2 days, the AUC of the theophylline was increased by 45% (from 189.9 to 274.9 micrograms.h/ml) and the total body clearance was reduced by 30%.

Care is also required (with monitoring changes in renal function) if administering Aciclovir 25 mg/ml Sterile Concentrate with drugs that affect other aspects or renal physiology (e,g, cyclosporine, tacrolimus) as they may influence the nephrotoxic effect of aciclovir.

4.6 Pregnancy And Lactation

Limited data are available on the use of aciclovir during pregnancy. Aciclovir should not be used during pregnancy unless the potential benefits to the patient outweigh the potential risk to the foetus.

Limited human data show that aciclovir is excreted in human breast milk. Aciclovir should only be administered to nursing mothers if the benefits to the mother outweigh the potential risks to the baby.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

Renal

Rapid increases in blood urea and creatinine levels may occasionally occur in patients given Aciclovir 25 mg/ml Sterile Concentrate. These are usually reversible but progression to acute renal failure can occur in rare cases. The rapid increases in blood urea and creatinine levels are believed to be related to peak plasma levels and the state of hydration of the patient. To avoid this effect the drug should not be given as an intravenous bolus injection but by slow infusion over a one hour period. Adequate hydration of the patient should be maintained.

The risk of renal damage is increased by concomitant use of other nephrotoxic drugs and pre-existing renal disease.

Renal impairment developing during treatment with Aciclovir 25 mg/ml Sterile Concentrate usually responds rapidly to rehydration of the patient and/or dosage reduction or withdrawal of the drug. Progression to acute renal failure, however, can occur in exceptional cases.

Skin

Local necrosis and inflammation have occurred when Aciclovir 25 mg/ml Sterile Concentrate has been inadvertently infused into extravascular tissues. Severe local inflammatory reactions or phlebitis have occurred at the injection site sometimes leading to breakdown of the skin. These local effects occur more frequently following inadvertent infusion of aciclovir into extravascular tissues.

Rashes and hives may occur.

Neurological

Reversible neurological reactions such as confusion, lethargy, hallucinations, agitation, tremors, somnolence, psychosis, convulsions and coma have been associated with Aciclovir 25 mg/ml Sterile Concentrate therapy. Reversible psychiatric effects and headaches have been reported less frequently.

Therefore aciclovir should be used with caution in patients with underlying neurological abnormalities. It should also be used with caution in patients who have manifested neurological reactions to cytotoxic drugs or are receiving concomitant interferon or intrathecal methotrexate.

Haematological

Increases in liver-related enzymes and fever have been reported in patients receiving Aciclovir 25 mg/ml Sterile Concentrate. Haemotological disorders including anaemia, thrombocytopenia and leucopoenia have been rarely reported

Other

Aciclovir should be used with caution in patients with significant hypoxia or serious hepatic or electrolyte abnormalities.

Other less frequent adverse effects reported in patients receiving therapy with Aciclovir 25 mg/ml Sterile Concentrate include, diaphoresis, haematuria, hypotension, nausea and vomiting.

In case of high doses, abdominal pain and thirst have been reported in patients who had been treated previously with aciclovir.

4.9 Overdose

Toxicity and treatment of overdosage

There is little experience concerning overdosage with aciclovir however single doses of Aciclovir 25 mg/ml Sterile Concentrate up to 80 mg/kg bodyweight have been inadvertently administered without adverse effects. Effects of overdosage may be expected to be similar in nature to those described under adverse reactions. Adequate hydration is essential to reduce the possibility of crystal formation in the urine. Aciclovir can be removed from the circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mode of action: Aciclovir is a synthetic acyclic purine nucleoside analogue (ATC J05A B01) with in vitro and in vivo inhibitory activity against human Herpes viruses, including Herpes simplex virus types 1 and 2 and Varicella zoster virus (VZV), Epstein Barr virus (EBV) and Cytomegalovirus (CMV). In cell culture aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV, and CMV.

The inhibitory activity of aciclovir for HSV-1, HSV-2, VZV and EBV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use aciclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV,VZV and EBV converts aciclovir to aciclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Aciclovir needs to be phosphorylated to the active compound aciclovir triphosphate, in order to become active against the virus. Aciclovir triphosphate acts as an inhibitor of, and a substrate for, the herpes specified DNA polymerase preventing further viral DNA synthesis.

5.2 Pharmacokinetic Properties

Pharmacokinetics: In adults, the terminal plasma half-life of aciclovir after the administration of Aciclovir 25 mg/ml Sterile Concentrate is about 3 hours. Aciclovir is widely distributed in tissues and body fluids. Approximately 75-80% of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. 9-carboxymethoxymethylguanine is the major significant metabolite of aciclovir and accounts for 10 to 15% of the dose excreted in the urine.

In adults, mean steady state peak (Cssmax) plasma concentrations following a one-hour infusion were ;

	2.5 mg/kg	5 mg/kg	10 mg/kg	15 mg/kg
Css max in µmol or in (µg/ml)	22.7 (5.1)	43.6 (9.8)	92 (20.7)	105 (23.6)
Css min, after 7 hours, in µmol or in (µg/ml)	2.2 (0.5)	3.1 (0.7)	10.2 (2.3)	8.8 (2.0)

In children over 1 year of age similar mean peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250 mg/m² was substituted for 5 mg/kg and a dose of 500 mg/m² was substituted for 10 mg/kg. In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 micromolar (13.8 microgram/ml) and the Cssmin. to be 10.1 micromolar (2.3 microgram/ml).

The terminal plasma half-life in neonates was approximately 4 hours. In the elderly, total body clearance falls with increasing age and is associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.

In patients with end stage renal failure the plasma half-life is increased, extending to a mean terminal half-life of approximately 20 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.

Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels.

Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

5.3 Preclinical Safety Data

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.

Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. Animal studies indicate that at high dose aciclovir is cytotoxic.

In a non-standard test in rats, foetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of (orally administered) aciclovir on fertility.

There is no experience of the effect of Aciclovir 25 mg/ml Sterile Concentrate on human fertility. Aciclovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium hydroxide and water for injections. In the manufacture of the finished product sodium hydroxide and / or hydrochloric acid are used for pH adjustment.

6.2 Incompatibilities

Aciclovir sodium is reported to be incompatible with solutions of amifostine, amsacrine, aztreonam, diltiazem hydrochloride, dobutamine hydrochloride, dopamine hydrochloride, fludarabine phosphate, foscarnet sodium, idarubicin hydrochloride, meropenem, morphine sulphate, ondansetron hydrochloride, pethidine hydrochloride, piperacillin sodium - tazobactam sodium, sargramostim and vinorelbine tartrate.

Do not use bacteriostatic water for injection containing parabens or benzyl alcohol. Biologic or colloidal fluids (e.g. blood products, protein containing solutions) are incompatible with aciclovir sodium.

6.3 Shelf Life

As packaged: 24 months.

After dilution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25 ^oC. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. When dilution is carried out under validated aseptic conditions, the product may be stored for a maximum of 12 hours at room temperature, below 25^oC.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Glass vials with butyl rubber stopper and an aluminium seal with a plastic 'flip-off' top. Packs of 5 vials (250 mg/10 ml) or (500 mg/20 ml) per carton, and as a single vial (1 g/40 ml) in a carton.

6.6 Special Precautions For Disposal And Other Handling

Aciclovir 25 mg/ml Sterile Concentrate contains no preservative. Dilution should therefore be carried out immediately before use under full aseptic conditions and any unused solution should be discarded.

Refrigeration is not recommended as precipitation may occur.

For adults, it is recommended that infusion bags containing 100 ml of infusion fluid are used, even when this would give an aciclovir concentration substantially below 0.5% w/v. Thus one 100 ml infusion bag may be used for any dose between 250 mg and 500 mg aciclovir but a second bag must be used for doses between 500 and 1000 mg. Aciclovir 25 mg/ml Sterile Concentrate should not be diluted to a concentration greater than 5 mg/ml (0.5%w/v) for administration by infusion. After addition of Aciclovir 25 mg/ml Sterile Concentrate to an infusion solution the mixture should be shaken to ensure thorough mixing.

For children and neonates, where it is advisable to keep the volume of infusion fluid to a minimum, it is recommended that dilution is on the basis of 4 ml of solution (100 mg aciclovir) added to 20 ml of infusion fluid.

When diluted in accordance with the recommended schedules, Aciclovir 25 mg/ml Sterile Concentrate is known to be compatible with the infusion fluids listed below:

Sodium Chloride Intravenous Infusion 0.9% w/v;

Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion ;

Sodium Chloride (0.9% w/v) and Glucose (5% w/v) Intravenous Infusion ;

Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) Intravenous Infusion ;

Compound Sodium Lactate Intravenous Infusion (Hartmann's Solution).

Aciclovir 25 mg/ml Sterile Concentrate when diluted in accordance with the above schedule will give an aciclovir concentration not greater than 0.5% w/v.

Aciclovir 25 mg/ml Sterile Concentrate contains no preservative.

Should any visible turbidity or crystallisation appear in the solution before or during infusion, the preparation should be discarded.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

8. Marketing Authorisation Number(S)

PL 04515/0098

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th June 1997

10. Date Of Revision Of The Text

19^th February 2008

Adcirca

1. Name Of The Medicinal Product

ADCIRCA* 20 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 20 mg tadalafil.

Excipients: Each coated tablet contains 245 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

Orange and almond shaped tablets, marked "4467" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

ADCIRCA is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1).

Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.

4.2 Posology And Method Of Administration

Method of administration:

ADCIRCA is available as 20 mg film-coated tablets for oral use.

Posology:

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

The recommended dose is 40 mg (2 x 20 mg) taken once daily with or without food.

Use in elderly patients:

Dose adjustments are not required in elderly patients.

Use in patients with renal impairment:

In patients with mild to moderate renal impairment a starting dose of 20 mg once per day is recommended. The dose may be increased to 40 mg once per day, based on individual efficacy and tolerability. In patients with severe renal impairment the use of ADCIRCA is not recommended (see sections 4.4 and 5.2).

Use in patients with hepatic impairment:

Due to limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B), following single doses of 10 mg, a starting dose of 20 mg once per day may be considered. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended (see sections 4.4 and 5.2).

Paediatric population:

The safety and efficacy of ADCIRCA in individuals below 18 years of age has not yet been established. No data are available.

4.3 Contraindications

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

Acute myocardial infarction within the last 90 days.

Severe hypotension (<90/50 mm Hg).

- In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of ADCIRCA to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

ADCIRCA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).

4.4 Special Warnings And Precautions For Use

The following groups of patients with cardiovascular disease were not included in PAH clinical trials:

- Patients with clinically significant aortic and mitral valve disease

- Patients with pericardial constriction

- Patients with restrictive or congestive cardiomyopathy

- Patients with significant left ventricular dysfunction

- Patients with life-threatening arrhythmias

- Patients with symptomatic coronary artery disease

- Patients with uncontrolled hypertension.

Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility of associated PVOD should be considered.

As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects.

Visual defects and cases of NAION have been reported in connection with the intake of ADCIRCA and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to consult a physician immediately (see section 4.3). Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, ADCIRCA is not recommended in patients with severe renal impairment.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of ADCIRCA is not recommended.

Priapism has been reported in men treated with PDE5 inhibitors. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

ADCIRCA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

In patients who are taking alpha₁ blockers, concomitant administration of ADCIRCA may lead to symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil and doxazosin is not recommended.

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended (see section 4.5).

For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended (see section 4.5).

The safety and efficacy of combinations of ADCIRCA and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Inform patients not to take ADCIRCA with these medications.

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).

ADCIRCA contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other substances on tadalafil

Cytochrome P450 Inhibitors

Azole Antifungals (e.g.,ketoconazole)

Ketoconazole (200 mg daily), increased tadalafil (10 mg) single-dose exposure (AUC) 2-fold and C_max by 15%, relative to the AUC and C_max values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single-dose exposure (AUC) 4-fold and C_max by 22%.

Protease inhibitors (e.g., ritonavir)

Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single-dose exposure (AUC) 2-fold with no change in C_max. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased C_max by 30%.

Cytochrome P450 Inducers

Endothelin-1 receptor antagonists (e.g., bosentan)

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42% and C_max by 27% following multiple dose co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.4 and 5.1). Tadalafil did not affect the exposure (AUC and C_max) of bosentan or its metabolites.

The safety and efficacy of combinations of ADCIRCA and other endothelin-1 receptor antagonists have not been studied.

Antimicrobial agents (e.g., rifampicin)

A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and C_max by 46%, relative to the AUC and C_max values for tadalafil alone (10 mg).

Effects of tadalafil on other medicinal products

Nitrates

In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Therefore, administration of ADCIRCA to patients who are using any form of organic nitrate is contraindicated (see section 4.3).

Anti-hypertensives (including Calcium channel blockers)

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore this combination is not recommended (see section 4.4).

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin.

In clinical pharmacology studies, the potential for tadalafil (10 and 20 mg) to augment the hypotensive effects of antihypertensive agents was examined. Major classes of antihypertensive agents were studied either as monotherapy or as part of combination therapy. In patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed compared to subjects whose blood pressure was well controlled, where the reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of doxazosin - see above) is, in general, minor and not likely to be clinically relevant.

Alcohol

Alcohol concentrations were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen after co-administration with alcohol. Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80-kg male) but in some subjects, postural dizziness and orthostatic hypotension were observed. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

CYP1A2 substrates (e.g., theophylline)

When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate.

CYP2C9 substrates (e.g., R-warfarin)

Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

Aspirin

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

P-glycoprotein substrates (e.g., digoxin)

Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.

Oral Contraceptive Pill

At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26% and C_max by 70% relative to oral contraceptive administered with placebo. There was no statistically significant effect of tadalafil on levonorgestrel which suggests the effect of ethinylestradiol is due to inhibition of gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.

Terbutaline

A similar increase in AUC and C_max seen with ethinylestradiol may be expected with oral administration of terbutaline, probably due to inhibition of gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.

4.6 Pregnancy And Lactation

There are limited data from the use of tadalafil in pregnant women. 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). As a precautionary measure, it is preferable to avoid the use of ADCIRCA during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. ADCIRCA should not be used during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effect on the ability to drive and use machines have been performed. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to ADCIRCA, before driving or operating machinery.

4.8 Undesirable Effects

a. Summary of the safety profile

The most commonly reported adverse reactions, occurring in

b. Tabulated summary of adverse reactions

In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (ADCIRCA 11%, placebo 16%). Three hundred and fifty seven (357) subjects who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily.

The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with ADCIRCA. Also included in the table are some adverse events/reactions which have been reported in clinical trials and/or post marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not known”, as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA.

Adverse reactions

Frequency estimate: Very common (

Very common (	Common (	Uncommon (	Rare (	Not known 1
Immune system disorders
	Hypersensitivity reactions5
Nervous system disorders
Headache7	Migraine5	Seizures5, Transient amnesia5		Stroke2 (including haemorrhagic events)
Eye disorders
	Blurred vision			Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect
Ear and labyrinth disorders
				Sudden hearing loss6
Cardiac disorders
	Chest pain2, Palpitations2, 5	Sudden cardiac death2, 5, Tachycardia2, 5		Unstable angina pectoris, Ventricular arrhythmia, Myocardial Infarction2
Vascular disorders
Flushing	Hypotension	Hypertension
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis (including nasal congestion, sinus congestion and rhinitis)	Epistaxis
Gastrointestinal disorders
Nausea, Dyspepsia (including abdominal pain/discomfort3)	Vomiting Gastroesophageal reflux
Skin and subcutaneous tissue disorders
	Rash	Urticaria5, Hyperhydrosis (sweating)5		Stevens-Johnson Syndrome, Exfoliative dermatitis
Musculoskeletal, connective tissue and bone disorders
Myalgia, Back pain Pain in extremity (including limb discomfort)
Reproductive system and breast disorders
	Increased uterine bleeding4	Priapism5		Prolonged erections
General disorders and administration site conditions
	Facial oedema, Chest pain2

¹ Events not reported in registration trials and cannot be estimated from the available data. The adverse reactions have been included in the table as a result of postmarketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction.

² Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors.

³ Actual MedDRA terms included are abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and stomach discomfort.

⁴ Clinical non-MedDRA term to include reports of abnormal/excessive menstrual bleeding conditions such as menorrhagia, metrorrhagia, menometrorrhagia, or vaginal haemorrhage.

⁵ The adverse reactions have been included in the table as a result of postmarketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction; and in addition, the frequency estimates are based on only 1 or 2 patients experiencing the adverse reaction in the pivotal placebo-controlled study of ADCIRCA.

⁶ Sudden decrease or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all PDE5 inhibitors, including tadalafil.

⁷ See section c)

c. Description of selected adverse reactions

Headache was the most commonly reported adverse reaction. Headache may occur at the beginning of therapy; and decreases over time even if treatment is continued.

4.9 Overdose

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients with erectile dysfunction. Adverse events were similar to those seen at lower doses.

In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis contributes negligibly to tadalafil elimination.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC Code: G04BE08.

Mechanism of action

Tadalafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations within the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of the pulmonary vascular smooth muscle cell and vasodilation of the pulmonary vascular bed.

Pharmacodynamic effects

Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is> 10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is> 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also> 10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Efficacy in patients with pulmonary arterial hypertension (PAH)

A randomised, double-blind, placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension. Allowed background therapy included bosentan (stable maintenance dose up to 125 mg twice daily) and chronic anticoagulation, digoxin, diuretics and oxygen. More than half (53.3%) of the subjects in the study were receiving concomitant bosentan therapy.

Patients were randomised to one of five treatment groups (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or placebo). Subjects were at least 12 years of age and had a diagnosis of PAH that was idiopathic, related to collagen disease, related to anorexigen use, related to human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of at least 1 year in duration of a congenital systemic-to-pulmonary shunt (for example, ventricular septal defect, patent ductus arteriosus). The mean age of all subjects was 54 years (range 14 to 90 years) with the majority of subjects being Caucasian (80.5%) and female (78.3%). Pulmonary arterial hypertension (PAH) etiologies were predominantly idiopathic PAH (61.0%) and related to collagen vascular disease (23.5%). The majority of subjects had a World Health Organization (WHO) Functional Class III (65.2%) or II (32.1%). The mean baseline 6-minute-walk-distance (6MWD) was 343.6 metres.

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance (6MWD). Only tadalafil 40 mg achieved the protocol defined level of significance with a placebo-adjusted median increase in 6MWD of 26 metres (p=0.0004; 95% CI: 9.5, 44.0; Pre-specified Hodges-Lehman method) (mean 33 metres, 95% CI: 15.2, 50.3). The improvement in walk distance was apparent from 8 weeks of treatment. Significant improvement (p<0.01) in the 6MWD was demonstrated at week 12 when the subjects were asked to delay taking study medication in order to reflect trough drug concentration. Results were generally consistent in subgroups according to age, gender, PAH aetiology and baseline WHO functional class and 6MWD. The placebo-adjusted median increase in 6MWD was 17 metres (p=0.09; 95% CI: -7.1, 43.0; Pre-specified Hodges-Lehman method) (mean 23 metres, 95% CI: -2.4, 47.8) in those patients who received tadalafil 40 mg in addition to their concomitant bosentan (n=39), and was 39 metres (p<0.01, 95% CI: 13.0, 66.0; Pre-specified Hodges-Lehman method) (mean 44 metres, 95% CI: 19.7, 69.0) in those patients who received tadalafil 40 mg alone (n=37).

The proportion of patients with improvement in WHO functional class by week 16 was similar in the tadalafil 40 mg and placebo groups (23% vs. 21%). The incidence of clinical worsening by week 16 in patients treated with tadalafil 40 mg (5%; 4 of 79 patients) was less than placebo (16%; 13 of 82 patients). Changes in the Borg dyspnoea score were small and non-significant with both placebo and tadalafil 40 mg.

Additionally, improvements compared to placebo were observed with tadalafil 40 mg in the physical functioning, role-physical, bodily pain, general health, vitality and social functioning domains of the SF-36. No improvements were observed in the role emotional and mental health domains of the SF-36. Improvements compared to placebo were observed with tadalafil 40 mg in the EuroQol (EQ-5D) US and UK index scores comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression components, and in the visual analogue scale (VAS).

Cardiopulmonary haemodynamics was performed in 93 patients. Tadalafil 40mg increased cardiac output (0.6 L/min) and reduced pulmonary artery pressures (-4.3mmHg) and pulmonary vascular resistance (-209dyn.s/cm⁵) compared to baseline (p<0.05). However, post hoc analyses demonstrated that changes from baseline in cardiopulmonary haemodynamic parameters for the tadalafil 40 mg treatment group were not significantly different compared to placebo.

Long-term treatment

357 patients from the placebo-controlled study entered a long-term extension study. Of these, 311 patients had been treated with tadalafil for at least 6 months and 293 for 1 year (median exposure 365 days; range 2 days to 415 days). For those patients for which there are data, the survival rate at 1 year is 96.4%. Additionally, 6 minute walk distance and WHO functional class status appeared to be stable in those treated with tadalafil for 1 year.

Tadalafil 20 mg administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate.

In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (< 0.1 %).

Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters such as motility, morphology and FSH.

5.2 Pharmacokinetic Properties

Absorption

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a median time of 4 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.

The rate and extent of absorption of tadalafil are not influenced by food, thus ADCIRCA may be taken with or without food. The time of dosing (morning versus evening after a single 10 mg administration) had no clinically relevant effects on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 77 l at steady state, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94 % of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.

Less than 0.0005 % of the administered dose appeared in the semen of healthy subjects.

Biotransformation

Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

Elimination

The mean oral clearance for tadalafil is 3.4 l/h at steady state and the mean terminal half-life is 16 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61 % of the dose) and to a lesser extent in the urine (approximately 36 % of the dose).

Linearity/non-linearity

Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Between 20 mg to 40 mg, a less than proportional increase in exposure is observed. During tadalafil 20 mg and 40 mg once daily dosing, steady-state plasma concentrations are attained within 5 days, and exposure is approximately 1.5 fold of that after a single dose.

Population pharmacokinetics

In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady state following 40 mg was 26% higher when compared to those of healthy volunteers. There were no clinically relevant differences in C_max compared to healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.

Special Populations

Elderly

Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25 % higher exposure (AUC) relative to healthy subjects aged 19 to 45 years after a 10 mg dose. This effect of age is not clinically significant and does not warrant a dose adjustment.

Renal insufficiency

In clinical pharmacology studies using single-dose tadalafil (5-20 mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end_max was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.

Hepatic insufficiency

Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, and therefore dosing of tadalafil in these patients is not recommended.

Patients with diabetes

Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC value for healthy subjects after a 10 mg dose. This difference in exposure does not warrant a dose adjustment.

Race

Pharmacokinetic studies have included subjects and patients from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.

Gender

In healthy female and male subjects following single dose and multiple-doses of tadalafil, no clinically relevant differences in exposure were observed. No dose adjustment is warranted.

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.

There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg dose.

There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7 – 18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

lactose monohydrate,

croscarmellose sodium,

hydroxypropylcellulose,

microcrystalline cellulose,

sodium laurilsulfate,

magnesium stearate.

Film-coat:

lactose monohydrate,

hypromellose,

triacetin,

titanium dioxide (E171),

iron oxide yellow (E172),

iron oxide red (E172),

talc.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store in the original package in order to protect from moisture. Do not store above 30°C.

6.5 Nature And Contents Of Container

Aluminium/PVC/PE/PCTFE blisters in cartons of 28 and 56 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

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

7. Marketing Authorisation Holder

Eli Lilly Nederland B.V.

Grootslag 1-5, NL-3991 RA, Houten

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/08/476/005 Adcirca 20 mg 28 tablets

EU/1/08/476/006 Adcirca 20 mg 56 tablets

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 1 October 2008

10. Date Of Revision Of The Text

03 November 2010

LEGAL CATEGORY

POM

*ADCIRCA (tadalafil) is a trademark of Eli Lilly and Company. AD3M

Anacal Rectal Ointment (Genus Pharmaceuticals)

1. Name Of The Medicinal Product

Anacal Rectal Ointment

2. Qualitative And Quantitative Composition

Mucopolysaccharide polysulphuric acid ester (Heparinoid) 0.2%w/w

Oxypolyethoxydodecane (Lauromacrogol 400) 5.0%w/w

3. Pharmaceutical Form

Rectal Ointment

4. Clinical Particulars

4.1 Therapeutic Indications

Anacal rectal ointment is indicated for the treatment of the following conditions:

Relief of symptoms associated with haemorrhoids (including perianal haematomas), perianal eczema, pruritus, anal fissure, proctitis, periproctitis, and aftercare of haemorrhoids treated by surgery or injection.

4.2 Posology And Method Of Administration

Adults and the elderly:

To be applied one to four times daily.

Children:

Not recommended.

4.3 Contraindications

Known sensitivity to any active or inactive component of the formulation.

Not recommended for use in children.

4.4 Special Warnings And Precautions For Use

If condition persists or worsens, seek medical advice.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is no evidence to suggest that Anacal Rectal Ointment should not be used during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None known.

4.9 Overdose

In the absence of any reports of the accidental ingestion of Anacal, no specific advice is available. General supportive measures may be appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mucopolysaccharide polysulphate ester is recognised as having:

A weak inhibitory effect on PGE₂ synthesis and an indirect effect on LTB₄ production based on in vitro studies.

Anti-coagulant activity: as a heparinoid.

Thrombolytic activity: through potentiation of urokinase activity.

Anti-exudatory activity: through inhibition of hyaluronidase.

Oxypolyethoxydodecane has both topical anaesthetic and anti-pruritic properties.

5.2 Pharmacokinetic Properties

Radiochemical studies of absorption following cutaneous application of mucopolysaccharide polysulphate have shown that between 0.3 and 4% of the mucopolysaccharide administered is absorbed by various tissues (other than the treated area) within the first 8 hours. Typically between 1.7% and 4.6% will be absorbed within 2 to 4 days. Animal studies have also shown that mucopolysaccharide is bound intracellularly within the subcutis. Peak serum concentrations following cutaneous application are below the threshold of physiological relevance for coagulation.

Mucopolysaccharide is excreted in the urine partly unchanged and partly as depolymerized, shorter chain length molecules.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyethylene highpolymer 1500 HSE

Liquid paraffin BP

Sorbitan stearate BP

Methylhydroxybenzoate BP

6.2 Incompatibilities

None.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 25ºC.

6.5 Nature And Contents Of Container

Lacquered aluminium tubes containing 30gm.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited,

Park View House

65 London Road,

Newbury,

Berkshire,

RG14 1JN

8. Marketing Authorisation Number(S)

PL 06831/0172

9. Date Of First Authorisation/Renewal Of The Authorisation

02 February 2006/ 18 March 2009

10. Date Of Revision Of The Text

18 March 2009

Adizem-SR tablets

Adizem-SR 120 mg prolonged-release tablets

Diltiazem hydrochloride

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.



• If you have any further questions, ask your doctor or pharmacist.



• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.



• If any of the side effects becomes serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What Adizem-SR tablets are and what they are used for

2. Before you take Adizem-SR tablets

3. How to take Adizem-SR tablets

4. Possible side effects

5. How to store Adizem-SR tablets

6. Further information

What Adizem-SR tablets are and what they are used for

These tablets have been prescribed for you to treat angina (chest pain caused by a reduction of oxygen to the heart muscle) or high blood pressure (hypertension). They contain the active ingredient diltiazem. Diltiazem belongs to a group of medicines called calcium antagonists. Calcium antagonists help more blood to reach the heart and reduce blood pressure. The other ingredients of Adizem-SR tablets are listed in section 6 of this leaflet.

Adizem-SR tablets are designed to work properly over 12 hours. If the tablets are crushed or chewed, the entire 12-hour dose may be absorbed rapidly into your body. This can be dangerous, causing serious problems such as an overdose.

Before you take Adizem-SR tablets

Do not take Adizem-SR tablets if you:

• are allergic (hypersensitive) to diltiazem or any of the other ingredients of the tablets (see section 6 ‘Further Information’);



• have a slow or irregular heart beat;



• have heart failure (which can cause shortness of breath or ankle swelling).

Children should not take these tablets.

Take special care with Adizem-SR tablets

Before treatment with Adizem-SR tablets tell your doctor or pharmacist if you have porphyria (a rare disease of the blood pigments).

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. If you take Adizem-SR tablets with some other medicines, the effect of Adizem-SR tablets or the other medicine may be changed.

Tell your doctor or pharmacist if you are taking:

• any other medicines for high blood pressure, such as beta blockers (for example atenolol), diuretics (for example bendrofluazide) or ACE inhibitors (examples include captopril and enalopril);



• medicines known as alpha blockers, which you may be taking to treat high blood pressure or prostate disorders (for example prazosin);



• any medicines which may cause low blood pressure or slow heart beat (for example aldesleukin to treat cancer of the kidneys, or antipsychotics to treat mental and behavioural disorders);



• ivabradine to treat angina;



• anti-arrhythmic medicines to treat an irregular or rapid heart beat (for example digoxin, amiodarone or beta-blockers);



• cilostazol to treat intermittent claudication (a condition that causes leg pain due to a restriction in blood supply to the muscles);



• medicines known as statins to reduce cholesterol levels in your blood (examples include simvastatin, atorvastatin or lovastatin);



• medicines known as H₂ antagonists to treat stomach ulcers, indigestion or heartburn, such as cimetidine or ranitidine;



• carbamazepine or phenytoin to treat seizures, fits or convulsions;



• medicines known as benzodiazepines to treat anxiety or help you sleep (examples include midazolam or triazolam);



• medicines known as barbiturates to either treat fits or to help you sleep (examples include phenobarbital or primidone);



• a specific type of antidepressant known as a tricyclic antidepressant (examples include amitriptyline or imipramine);



• rifampicin to treat tuberculosis;



• ciclosporin, sirolimus or tacrolimus to prevent organ transplant rejection or treat other immune system disorders;



• a specific type of medicine known as a protease inhibitor to treat HIV (examples include atazanavir or ritonavir);



• dantrolene (a muscle relaxant);



• theophylline to treat breathing problems such as asthma.

Also tell your doctor if you have recently been given an anaesthetic.

Taking Adizem-SR tablets with alcohol

Taking Adizem-SR tablets at the same time as an alcoholic drink is not recommended.

Pregnancy and breastfeeding

Do not take Adizem-SR tablets if you are pregnant, likely to become pregnant or are breastfeeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

The capsules may cause a number of side effects such as dizziness which could affect your ability to drive (see section 4 for a full list of side effects). These are usually most noticeable when you start taking the capsules, or when changing to higher dose. If you are affected you should not drive or operate machinery.

Important information about some of the ingredients of Adizem-SR tablets

These tablets contain sucrose and lactose which are forms of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking these tablets.

How to take Adizem-SR tablets

Always take Adizem-SR tablets exactly as your doctor has told you. The label on your medicine will tell you how many tablets to take and how often.

The usual dose is one tablet twice daily. However, if you are elderly or have kidney or liver problems then you may need to start on a lower dose. Your doctor will decide how many tablets you should take.

Children should not take these tablets.

Do not exceed the dose recommended by your doctor. You should check with your doctor or pharmacist if you are not sure.

Swallow your tablets whole with a glass of water. Do not chew or crush the tablets.

You should take your tablets every 12 hours. For instance, if you take a tablet at 8 o’clock in the morning, you should take your next tablet at 8 o’clock in the evening.

If you take more Adizem-SR tablets than you should or if someone accidentally swallows your tablets

Call your doctor or hospital straight away. People who have taken an overdose may become very unwell, feel faint, have a slow heart beat and lose consciousness. They may need emergency treatment in hospital. When seeking medical attention make sure that you take this leaflet and any remaining tablets with you to show to the doctor.

If you forget to take Adizem-SR tablets

If you remember within 4 hours of the time your tablet was due, take your tablet straight away. Take your next tablet at your normal time. If you are more than 4 hours late, please call your doctor or pharmacist for advice. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Adizem-SR tablets

You should not stop taking these tablets unless your doctor tells you to. If you want to stop taking your tablets, discuss this with your doctor first.

If you have any further questions on the use of Adizem-SR tablets ask your doctor or pharmacist.

Adizem-SR tablets Side Effects

Like all medicines, Adizem-SR tablets can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions, although serious allergic reactions are rare. Tell your doctor immediately if you get swelling of the face or throat.

Common side effects (probably affecting more than 1 in 100 people taking Adizem-SR tablets)

• Gastrointestinal disorders (e.g. upset stomach), feeling sick.



• Dizziness, headache.



• Tiredness.



• Swelling of the legs.



• Facial flushing (redness of the face).



• Low blood pressure.

Uncommon side effects (probably affecting fewer than 1 in 100 people taking Adizem-SR tablets)

• A reduction in blood platelets which increases the risk of bleeding or bruising.



• Changes in muscle tone and/or abnormalities of movement.



• Skin problems such as an increased sensitivity to sunlight, itching, rash, redness, swelling, severe flaking or peeling of the skin.



• Inflammation of blood vessels (often with skin rash).



• A fast, slow or irregular heart beat.



• Bleeding, tender or enlarged gums.



• Breast enlargement in men.



• Inflammation of the liver.

Uncommonly, Adizem-SR tablets may affect the results of blood tests to check that your liver is working properly.

If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Adizem-SR tablets

Keep out of the reach and sight of children.

Do not use any tablets after the expiry date which is stated on the carton. EXP 08 2010 means that you should not take the tablets after the last day of that month i.e. August 2010.

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

Do not take your tablets if they are broken or crushed as this can be dangerous and can cause serious problems such as overdose.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Adizem-SR tablets contain

The active ingredient is diltiazem hydrochloride. Each tablet contains 120 mg of diltiazem hydrochloride.

The other ingredients are:

• Lactose



• Hydrogenated castor oil



• Colloidal aluminium hydroxide



• Acrylic resin



• Talc



• Magnesium stearate



• Hypromellose



• Sucrose



• Glycerol



• Titanium dioxide (E171)



• Polysorbate 80

What Adizem-SR tablets look like and the contents of the pack

Adizem-SR tablets are white, capsule shaped, film-coated tablets marked 120/DL on one side and with a scoreline on the other.

In each box there are 56 tablets.

Marketing Authorisation Holder and Manufacturer

The tablets are made by

Bard Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

for the marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call the RNIB Medicine Information line (free of charge) on:

0800 198 5000

You will need to give details of the product name and reference number.

These are as follows:

Product name: Adizem-SR prolonged-release tablets

Reference number: 16950/0009

This leaflet was last revised in October 2009

Adizem, NAPP and the NAPP device (logo) are Registered Trade Marks.

© 2008-2009 Napp Pharmaceuticals Limited.

P0079-A R4V1 UK AW 28-10-09

Adizem SR tablets P0079-A R4V1 UK AW 28-10-09 (combined versions R2 & R3) 3(combined versions R2 & R3)

ALLERcalm Allergy Relief Tablets

1. Name Of The Medicinal Product

1. CHLORPHENAMINE TABLETS BP 4mg

2. Alpharma Chlorphenamine Hayfever & Allergy Relief Tablets

3. Vantage Chlorphenamine Hayfever & Allergy Relief Tablets

4. ALLERcalm Allergy Relief Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 4mg Chlorphenamine Maleate.

3. Pharmaceutical Form

Yellow uncoated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

1) For the symptomatic control of all allergic conditions which are responsive to antihistamines, including hay fever, urticaria, vasomotor rhinitis, angioneurotic oedema, food allergy, drug and serum reactions, insect bites.

4.2 Posology And Method Of Administration

Posology

Adults: 1 tablet every four or six hours to a maximum daily dose of 24mg.

Not recommended for children under 12 years of age unless otherwise directed by a practitioner.

Elderly: As in adults, but the elderly are prone to confusional psychosis and other neurological anticholinergic effects.

Method of Administration

For oral administration.

4.3 Contraindications

Hypersensitivity to antihistamines; patients who have received therapy with MAOI's within the previous fourteen days.

4.4 Special Warnings And Precautions For Use

In common with other drugs having anticholinergic effects, Chlorphenamine should be used with caution in epilepsy, prostatic hypertrophy, glaucoma, hepatic disease, bronchitis, bronchiectasis, thyrotoxicosis, raised intra-ocular pressure, severe hypertension or cardiovascular disease and bronchial asthma.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Chlorphenamine may have an additive effect when used concurrently with hypnotics and anxiolytics causing potentiation of drowsiness. A similar additive effect will result from concurrent usage of alcohol with Chlorphenamine. MAOI therapy intensifies the anticholinergic effects of Chlorphenamine. Chlorphenamine inhibits phenytoin metabolism and can lead to phenytoin toxicity.

4.6 Pregnancy And Lactation

The safety of Chlorphenamine in pregnancy has not been established. Chlorphenamine should therefore only be used when clearly required and when potential benefits outweigh the potential unknown risks to the foetus. Use during the third trimester may result in reactions in the newborn or premature neonates.

Small amounts of antihistamines are excreted in breast milk. Use by nursing mothers is not recommended because of the risks of adverse effects in the infant.

Antihistamines may inhibit lactation.

4.7 Effects On Ability To Drive And Use Machines

The anticholinergic properties of Chlorphenamine may cause drowsiness, dizziness, blurred vision and psychomotor impairment, which can seriously hamper the patient's ability to drive and use machinery.

4.8 Undesirable Effects

Sedation varying from slight drowsiness to deep sleep. Inability to concentrate, lassitude, blurred vision, GI disturbances such as nausea, vomiting and diarrhoea may occasionally occur. Urinary retention, headaches, dryness of the mouth. Dizziness, palpitation, tachycardia, arrhythmias, hypotension, tightness of the chest, abdominal pain, dyspepsia, anorexia, hepatic including jaundice, thickening of the bronchial secretions, haemolytic anaemia and other blood dyscrasias infrequently occur.

Allergic reactions including exfoliative dermatitis, photosensitivity and skin reactions. Urticaria, twitching, muscular weakness and in co-ordination. Tinnitus, depression, irritability and nightmares infrequently occur.

Paradoxical excitation in children and confusional psychosis in the elderly can occur.

The effects of alcohol may be increased. Children and the elderly are more likely to experience the neurological anticholinergic effects.

4.9 Overdose

The estimated lethal dose of Chlorphenamine is 25-50mg/kg body weight.

Symptoms and signs include sedation, paradoxical stimulation of the CNS, toxic psychosis, seizures, apnoea, convulsions, anticholinergic effects, dystonic reactions and cardiovascular collapse including arrhythmias.

Treatment includes gastric lavage or emesis using ipecacuanha syrup. Following these measures activated charcoal and cathartics may be administered to minimise absorption. Other symptomatic and supportive measures should be provided with special attention to cardiac, respiratory, renal and hepatic functions and fluid and electrolyte balance.

Treat hypotension and arrhythmias vigorously. CNS convulsions may be treated with IV diazepam or phenytoin. Haemoperfusion may be used in severe cases.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Chlorphenamine Maleate is an antihistamine.

5.2 Pharmacokinetic Properties

Chlorphenamine Maleate is an alkylamine derivative with a plasma half-life of up to 42 hours which is extensively metabolised in the liver and excreted almost exclusively in the urine.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Also contains: calcium sulphate, magnesium stearate, maize starch, E172, E460.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 7, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0209

9. Date Of First Authorisation/Renewal Of The Authorisation

9.5.86

Renewed: 20.10.02

10. Date Of Revision Of The Text

June 2007