Lodotra® 1 mg, 2 mg and 5 mg modified-release tablets

1. Name Of The Medicinal Product

Lodotra 1 mg, 2 mg and 5 mg modified-release tablets

2. Qualitative And Quantitative Composition

Each modified-release tablet contains 1 mg, 2 mg or 5 mg prednisone.

1 mg tablet: Also contains 40.7 mg of lactose.

2 mg tablet: Also contains 39.7 mg of lactose.

5 mg tablet: Also contains 36.9 mg of lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Modified-release tablet

The 1 mg tablets are pale yellowish-white, cylindrical tablets with “NP1” embossed on one side.

The 2 mg tablets are yellowish-white, cylindrical tablets with “NP2” embossed on one side.

The 5 mg tablets are light yellow, cylindrical tablets with “NP5” embossed on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Lodotra is indicated for the treatment of moderate to severe, active rheumatoid arthritis in adults particularly when accompanied by morning stiffness.

4.2 Posology And Method Of Administration

The appropriate dose depends on the severity of the condition and the individual response of the patient. In general, for the initiation of the therapy 10 mg prednisone is recommended. In certain cases, a higher initial dose might be required (e.g. 15 or 20 mg prednisone). Depending on the clinical symptoms and the patient's response, the initial dose can be reduced in steps to a lower maintenance dose.

When changing over from the standard regimen (glucocorticoid administration in the morning) to Lodotra administered at bedtime (at about 10 pm), the same dose (in mg prednisone equivalent) should be maintained. Following the change-over, the dose may be adjusted according to the clinical situation.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available. For long-term therapy of rheumatoid arthritis, the individual dose of up to 10 mg prednisone daily should be adjusted according to the severity of the course of the disease.

Depending on the treatment result, the dose can be reduced in steps of 1 mg every 2 - 4 weeks to reach the appropriate maintenance dose.

In order to discontinue the therapy with Lodotra, the dose should be reduced in steps of 1 mg every 2 - 4 weeks, with monitoring of pituitary-adrenal axis parameters if necessary.

Method of Administration:

Lodotra should be taken at bedtime (at about 10 pm), with or after the evening meal and be swallowed whole with sufficient liquid. If more than 2 - 3 hours have passed since the evening meal, it is recommended to take Lodotra with a light meal or snack (e.g. a slice of bread with ham or cheese). Lodotra should not be administered in the fasted state. This could result in a reduced bioavailability.

Lodotra is designed to release the active substance with a delay of approximately 4 - 6 hours after intake, the release of the active substance and the pharmacological effects will start during the night.

Lodotra modified-release tablets consist of a prednisone-containing core and an inert coating. Delayed release of prednisone is dependent on an intact coating. For this reason, the modified-release tablets are not to be broken, divided or chewed.

Because of insufficient data on tolerability and efficacy, the use in children and adolescents is not recommended.

In patients with hypothyroidism or hepatic cirrhosis, comparatively low doses may be sufficient or a dose reduction may be necessary.

4.3 Contraindications

Lodotra is contraindicated in patients with hypersensitivity to prednisone or to any of the excipients (see section 6.1).

4.4 Special Warnings And Precautions For Use

A prednisone-based pharmacotherapy should only be given when absolutely necessary and should be accompanied by appropriate anti-infectious therapy in the presence of the following conditions:

- Acute viral infections (herpes zoster, herpes simplex, varicella, herpetic keratitis),

- HBsAg-positive chronic active hepatitis,

- Approximately 8 weeks before and 2 weeks after immunisation with live vaccines,

- Systemic mycoses and parasitoses (e.g. nematodes),

- Poliomyelitis,

- Lymphadenitis following BCG inoculation,

- Acute and chronic bacterial infections,

History of tuberculosis (caution: reactivation!) Due to their immunosuppressive properties glucocorticoids can induce or aggravate infections. Such patients should be monitored carefully e.g. by performing a tuberculin test. Patients at special risk should receive a tuberculostatic treatment.

In addition, a prednisone-based pharmacotherapy should only be given when necessary and should be accompanied if required by appropriate therapy in the presence of the following conditions:

- Gastrointestinal ulcers,

- Severe osteoporosis and osteomalacia

- Hypertension that is difficult to control,

- Severe diabetes mellitus,

- Psychiatric disorders (also if in patient's history),

- Narrow- and wide-angle glaucoma,

- Corneal ulcers and corneal injuries.

Because of the risk of intestinal perforation, prednisone may only be used if absolutely necessary and with adequate monitoring in cases of:

- Severe ulcerative colitis with imminent perforation,

- Diverticulitis,

- Entero-anastomoses (immediately postoperative).

Lodotra cannot achieve the desired blood concentration of prednisone if taken under fasting conditions. Therefore, Lodotra should always be taken with or after the evening meal in order to ensure sufficient efficacy. In addition, low plasma concentrations may occur in 6% -7% of Lodotra doses as observed across all pharmacokinetic studies and 11% in a single pharmacokinetic study when taken according to the recommendations. This should be considered if Lodotra is not sufficiently effective. In these situations a switch to a conventional immediate-release formulation may be considered.

Lodotra should not be substituted by prednisone immediate-release tablets in the same administration regime because of Lodotra's delayed release mechanism.

In case of substitution, termination, or discontinuing prolonged treatment, the following risks must be considered: Recurrence of the rheumatoid arthritis disease activity, acute adrenal failure (especially in stressful situations, e. g. during infections, after accidents, with increased physical strain), cortisone withdrawal syndrome.

Lodotra should not be given as for acute indications instead of prednisone immediate-release tablets due to its pharmacological properties.

During the use of Lodotra, a possibly increased need for insulin or oral anti-diabetics should be considered. Patients with diabetes mellitus should therefore be treated under close monitoring.

During the treatment with Lodotra, regular blood pressure checks are required in patients with hypertension that is difficult to control.

Patients with severe cardiac insufficiency have to be closely monitored because of the risk of deterioration of the condition.

Sleep disorder is documented to occur more frequently with Lodotra than with conventional immediate release formulations which are taken in the morning. If insomnia occurs and does not improve, a switch to a conventional immediate release formulation may be advisable.

The treatment with Lodotra can also mask signs and symptoms of an existing or developing infection and thus may render diagnostic efforts more difficult.

Even with low doses, long-term use of Lodotra results in an increased risk of infection. These possible infections may also be brought about by microorganisms that rarely cause infection under normal circumstances (so-called opportunistic infections).

Certain viral diseases (varicella, measles) may take a more severe course in patients treated with glucocorticoids. Immunosuppressed individuals without prior varicella or measles infection are at particular risk. If such individuals, while being treated with Lodotra, have contact with persons infected with varicella or measles, a preventive treatment should be initiated, if required.

Vaccinations with inactivated vaccines are generally possible. However, it has to be taken into account that the immune response and consequently the success of the vaccination may be impaired with higher doses of glucocorticoids.

In case of long-term therapy with Lodotra, regular medical follow-ups (including ophthalmologic examinations at three month intervals) are indicated; if comparatively high doses are given, sufficient supply of potassium supplements and restriction of sodium have to be ensured and serum potassium levels have to be monitored.

If during the treatment with Lodotra high levels of physical stress are caused by certain events (accidents, surgical procedure etc.), a temporary dose increase may become necessary.

Depending on the duration of the treatment and the dosage used, a negative impact on calcium metabolism must be expected. Osteoporosis prophylaxis is therefore recommended and is particularly important if other risk factors are present (including familial predisposition, advanced age, postmenopausal status, insufficient intake of protein and calcium, excessive smoking, excessive alcohol consumption, as well as reduced physical activity). The prophylaxis is based on a sufficient supply of calcium and vitamin D, as well as on physical activity. In case of pre-existing osteoporosis, an additional therapy should be considered.

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

When using high doses of prednisolone for an extended period of time (30 mg/day for a minimum of 4 weeks), reversible disturbances of spermatogenesis were observed that persisted for several months after discontinuation of the medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Cardiac glycosides: The effect of the glycosides can be enhanced by potassium deficiency.

Saluretics/laxatives: Potassium excretion is enhanced.

Antidiabetic agents: The blood sugar lowering effect is reduced.

Coumarin derivatives: The efficacy of coumarin anticoagulants may be reduced or enhanced.

Non-steroidal antiphlogistic/antirheumatic agents, salicylates and indomethacin: The risk of gastrointestinal haemorrhages is increased.

Non-depolarising muscle relaxants: Muscle relaxation may be prolonged.

Atropine and other anticholinergics: The concurrent use of Lodotra may result in additional increases in intraocular pressure.

Praziquantel: Glucocorticoids may lower the praziquantel concentrations in the blood.

Chloroquine, hydroxychloroquine, mefloquine: There is an increased risk of occurrence of myopathies, cardiomyopathies.

Somatropin: The efficacy of somatropin may be reduced.

Oestrogens (e.g. oral contraceptives): May enhance the efficacy of glucocorticoids.

Liquorice: Inhibition of the metabolism of glucocorticoids is possible.

Rifampicin, phenytoin, barbiturates, bupropion and primidone: The efficacy of glucocorticoids is reduced.

Cyclosporine: The blood levels of cyclosporine are increased. There is an increased risk of seizures.

Amphotericine B: The risk of hypokalaemia may be increased.

Cyclophosphamide: The effects of cyclophosphamide may be enhanced.

ACE inhibitors: Increased risk of occurrence of blood count changes.

Aluminium and magnesium antacids: The absorption of glucocorticoids is reduced. However, due to the delayed release mechanism of Lodotra an interaction between prednisone and aluminium/magnesium antacids is unlikely.

Impact on diagnostic methods: Skin reactions caused by allergy testing may be suppressed. The TSH increase following the administration of protirelin may be reduced.

4.6 Pregnancy And Lactation

During pregnancy, Lodotra should only be used when the benefits outweigh the potential risks. The lowest effective dose of Lodotra needed to maintain adequate disease control should be used.

Animal studies indicate that administration of pharmacological doses of glucocorticoids during pregnancy may increase the foetus risk of intrauterine growth retardation, adult cardiovascular and/or metabolic disease and may have an effect on the glucocorticoid receptor density, and neurotransmitter turnover or neurobehavioural development.

Prednisone has caused cleft palate formation in animal experiments (see section 5.3). There is an ongoing discussion on the possibility of an increased risk of oral cleft formation in the human foetus as a result of the administration of glucocorticoids during the first trimester.

If glucocorticoids are administered towards the end of pregnancy, there is a risk of atrophy of the foetal adrenal cortex, which may necessitate replacement therapy in the newborn, which has to be slowly reduced.

Glucocorticoids pass in small amounts into breast milk (up to 0.23 % of an individual dose). For doses up to 10 mg daily, the amount taken via breast milk lies below the detection threshold. So far, no damage to infants has been reported. Nevertheless, glucocorticoids should only be prescribed when the benefits to mother and child outweigh the risks.

Because the milk/plasma concentration ratio increases with doses above 10 mg/day (e.g. 25 % of the serum concentration are found in the breast milk with 80 mg prednisone daily), it is recommended to discontinue breastfeeding in such cases.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The frequency and severity of the undesirable effects listed below depend on dosage and duration of treatment. In the recommended dose range for Lodotra (low-dose corticoid therapy with daily doses ranging from 1 to 10 mg), the listed undesirable effects occur less frequently with lower severity compared to doses above 10 mg.

The following undesirable effects may occur depending on the duration of treatment and the dosage:

very common (

Blood and lymphatic system disorders:

Common: Moderate leucocytosis, lymphopoenia, eosinopoenia, polycythaemia

Immune system disorders:

Common: Reduced immune defence, masking of infections, exacerbation of latent infections

Rare: Allergic reactions

Endocrine disorders:

Common: Adrenal suppression and induction of Cushing's syndrome (typical symptoms: moon-shaped face, upper body obesity and plethora)

Rare: Disturbed sexual hormone secretion (amenorrhoea, impotence), disturbance of the thyroid function

Metabolism and nutritional disorders:

Common: Sodium retention with oedema, increased potassium excretion (caution: arrhythmias), increased appetite and weight gain, reduced glucose tolerance, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia

Psychiatric disorders:

Common: Insomnia

Rare: Depression, irritability, euphoria, increased impulse, psychosis

Nervous system disorders:

Common: Headache

Rare: Pseudotumor cerebri, manifestation of a latent epilepsy and increased predisposition to develop seizures in cases of manifest epilepsy

Eye disorders:

Common: Cataract, especially with posterior subcapsular opacity, glaucoma

Rare: Aggravation of symptoms associated with corneal ulcer, promotion of viral, fungal and bacterial eye inflammations

Vascular disorders:

Uncommon: Hypertension, increased risk of arteriosclerosis and thrombosis, vasculitis (also as withdrawal syndrome following long-term therapy)

Disorders of the gastrointestinal tract:

Uncommon (no concomitant NSAIDs): Gastrointestinal ulcerations, gastrointestinal haemorrhages

Rare: Pancreatitis

Skin and subcutaneous tissue disorders:

Common: Striae rubrae, atrophy, telangiectasia, increased capillary fragility, petechiae, ecchymoses

Uncommon: Hypertrichosis, steroid acne, delayed healing of wounds, rosacea-like (perioral) dermatitis, changes in skin pigmentation

Rare: Hypersensitivity reactions, e.g. drug exanthema

Musculoskeletal and connective tissue disorders:

Common: Muscular atrophy and weakness, osteoporosis (dose-related, may occur even with short-term use)

Rare: Aseptic osteonecrosis (humeral and femoral head)

4.9 Overdose

Acute intoxications with Lodotra are not known. In case of overdosing, an increase in undesirable effects, especially endocrine, metabolic and electrolyte-related effects, can be expected (see section 4.8).

There is no known antidote for prednisone.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Glucocorticoids

ATC code: H02AB07

Prednisone is a non-fluorinated glucocorticoid for systemic therapy.

Prednisone shows a dose-dependent effect on the metabolism of almost all tissues. Under physiological conditions, these effects are vital to maintain homoeostasis of the organism at rest and under stress, as well as for the control of the activities of the immune system.

In doses typically prescribed for Lodotra, prednisone has an immediate anti-inflammatory (antiexsudative and antiproliferative) effect and a delayed immunosuppressive effect. It inhibits chemotaxis and the activity of immune cells as well as the release and effect of mediators of inflammatory and immune reactions, e.g. of lysosomal enzymes, prostaglandins and leucotrienes.

Prolonged therapy with high doses results in impaired response of the immune system and of the adrenal cortex. The mineralotropic effect that is pronounced in hydrocortisone is still detectable in prednisone and may require monitoring of serum electrolyte levels.

In patients with rheumatoid arthritis, pro-inflammatory cytokines such as the interleukins IL-1 and IL-6 and tumor necrosis factor alpha (TNFα) reach peak plasma levels in the early morning hours (e.g. IL- 6 between 7 to 8 am). Cytokine concentrations were shown to decrease after administration of Lodotra and subsequent night-time release of prednisone (with start of absorption between 2 - 4 am and Cmax between 4 - 6 am).

The efficacy and safety of Lodotra was assessed in two randomised, double-blind controlled studies in patients with active rheumatoid arthritis.

In the first study, a multi-centre randomised double-blind phase III study of 12 week duration in a total of 288 patients pre-treated with prednisone or prednisolone, the group switching to Lodotra at the same dose showed a mean reduction of 23% in the duration of morning stiffness whereas the duration in the reference group did not change. Details are presented in the following table.

Relative change in the duration of morning stiffness after 12 weeks of treatment:

Relative change [%]	Lodotra (n = 125)	Prednisone IR (n = 129)
Mean (SD) Median (min, max)	–23 (89) –34 (–100, 500)	0 (89) –13 (–100, 610)

In a subsequent open label extension phase (9 months treatment) the mean relative change in the duration of morning stiffness compared to baseline was about −50%.

Change in the duration of morning stiffness after 12 months treatment with Lodotra

Duration of morning stiffness [min]	Lodotra
Mean (SD)	N
0 months Start of the study	156 (97)	107
12 months End of open label phase	74 (92)	96

In the same study, after 12 weeks of treatment, a median decrease of the pro-inflammatory cytokine IL-6 of 29 % was observed in the group treated with Lodotra, whereas no change was observed in the comparator group who received standard prednisone. After 12 months of treatment with Lodotra the IL-6 level remains stable.

Change in the IL-6 level after 12 months

IL-6 [IU/L]	Lodotra
median (min, max)	N
0 months Start of the study	860 (200, 23000)	142
12 months End of open label phase	470 (200, 18300)	103

Values < 200 IU/L were set to 200 IU/L for statistical analyses

The efficacy of Lodotra given on top of a DMARD was confirmed in a second randomised, placebo-controlled trial in patients insufficiently responding to DMARD therapy alone. At 12 weeks the Lodotra patients had a significantly higher ACR20 and ACR50 response rate (46.8% and 22.1%, respectively) compared to placebo patients (29.4% and 10.1%, respectively). There was also a greater mean change in DAS 28 scores from baseline (5.2 for the Lodotra group and 5.1 for the placebo group) to week 12 in the Lodotra group (−1.2 points) as compared with that seen in the placebo group (−0.7 point change).

In addition, after 12 weeks of therapy the mean duration of morning stiffness was 86.0 minutes (-66 minutes change) in the Lodotra group and 114.1 minutes (-42.6 minutes change) in the placebo group. Lodotra could be safely used in combination with other DMARDs.

5.2 Pharmacokinetic Properties

Absorption:

Lodotra are prednisone-containing modified-release tablets. Prednisone is released between 4 - 6 hours following intake of Lodotra. Subsequently, prednisone is rapidly and almost completely absorbed.

Distribution:

Peak serum levels are reached approximately 6 - 9 hours after intake.

Metabolism:

More than 80 % of the prednisone is converted to prednisolone by first-pass hepatic metabolism. The ratio of prednisone to prednisolone is approximately 1:6 to 1:10. Prednisone itself exerts negligible pharmacologic effects. Prednisolone is the active metabolite. The compounds are reversibly bound to plasma proteins with high affinity for transcortin (corticosteroid binding globulin, CBG) and low affinity for plasma albumin.

In the low dose range (up to 5 mg), approximately 6% of free prednisolone is present. Metabolic elimination is dose linear in this range. In the dose range above 10 mg, the binding capacity of transcortin is increasingly exhausted and more free prednisolone is present. This may result in a faster metabolic elimination.

Elimination:

Prednisolone is primarily eliminated by hepatic metabolism, to approximately 70 % by glucoronidation and to approximately 30 % by sulphatation. There is also conversion to 11ß, 17ß-dihydroxyandrosta-1,4-dien-3-one and to 1,4-pregnadien-20-ol. The metabolites exhibit no hormonal activity and undergo primarily renal elimination. Negligible amounts of prednisone and prednisolone are found unchanged in the urine. The plasma elimination half-life of prednis(ol)one is approximately 3 hours. In patients with severe hepatic dysfunction the half-life may be prolonged and a dose reduction should be considered. The duration of the biological effects of prednis(ol)one exceeds the duration of the presence in the serum.

Bioavailability:

A bioavailability study in 27 healthy subjects conducted in 2003 revealed the following results in comparison with a prednisone immediate-release tablet:

Parameter	Lodotra 5 mg: 2.5 hours after a light meal	Lodotra 5 mg: Immediately after a meal	Reference preparation 5 mg fasted
Maximum plasma concentration (Cmax): ng/ml	20.2 (18.5; 21.9)	21.8 (20.0; 23.7)	20.7 (19.0; 22.5)
Time of maximum plasma concentration (tmax): h	6.0 (4.5; 10.0)	6.5 (4.5; 9.0)	2.0 (1.0; 4.0)
Duration of the delay of drug release (tlag): h	4.0 (3.5; 5.0)	3.5 (2.0; 5.5)	0.0 (0.0; 0.5)
Area under the concentration-time curve (AUC 0–): ng x h/ml	110 (101; 119)	123 (114; 133)	109 (101; 118)

Values are least-square geometric means and range

Figure: Mean plasma levels of prednisone after a single dose of 5 mg prednisone administered as Lodotra 5 mg or an immediate-release tablet. 5 mg immediate-release tablet (A: fasted, intake at 2 am), Lodotra 5 mg (B: 2.5 hours after a light evening meal) and Lodotra 5 mg (C: immediately after a full evening meal).

The plasma concentration profiles of Lodotra are very similar to an immediate-release tablet, with the important difference that the Lodotra profile is delayed with 4 – 6 hours after drug intake. Lower plasma concentrations have been observed in 6-7% of doses.

Dose proportionality was demonstrated for Lodotra 1 mg, 2 mg and 5 mg based on AUC and C_max.

5.3 Preclinical Safety Data

Subchronic/chronic toxicity

Light and electron microscopic changes in the Langerhans' islet cells of rats were observed following daily intraperitoneal administration of 33 mg/kg bw over 7 to 14 days in rats. In rabbits, experimental liver damage could be produced by administering 2 to 3 mg/kg bw/day for 2 to 4 weeks. Histotoxic effects (myonecroses) were reported following several weeks of administration of 0.5 to 5 mg/kg bw in guinea pigs and 4 mg/kg bw in dogs.

Mutagenic and tumour-forming potential

The toxicity observed in animal studies with prednisone was associated with exaggerated pharmacological activity. No genotoxic effects of prednisone have been observed in conventional genotoxicity tests.

Reproductive toxicity

In animal reproduction studies, glucocorticoids such as prednisone have been shown to induce malformations (cleft palate, skeletal malformations). With parenteral administration, minor anomalies of skull, jaw and tongue were found in rats. Intrauterine growth retardation was observed (also see section 4.6).

Similar effects are considered unlikely to occur in patients at therapeutic doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Colloidal anhydrous silica

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Povidone K 29/32

Red ferric oxide E 172

Tablet shell:

Colloidal anhydrous silica

Calcium hydrogen phosphate dihydrate

Glycerol dibehenate

Magnesium stearate

Povidone K 29/32

Yellow ferric oxide E 172

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Container with 30 and 100 modified-release tablets

White bottle made of high-density polyethylene (HDPE). Screw cap with three elevated points arranged around the rim to facilitate easy opening made of HDPE.

Pack sizes:

1 mg tablets Bottles with 30 modified release tablets

2 mg and 5 mg tablets Bottles with 30 and 100 modified release tablets

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

United Kingdom

8. Marketing Authorisation Number(S)

PL 16950/0173 - 0175

9. Date Of First Authorisation/Renewal Of The Authorisation

30 April 2009

10. Date Of Revision Of The Text

June 2011

® Lodotra is a registered trade mark of Horizon Pharma AG, and is used under licence.

NAPP and the 'NAPP' device (logo) are registered trade marks of the Napp Pharmaceutical Group.

© 2010 - 2011 Napp Pharmaceuticals Limited.

Lorazepam 1mg Tablets

1. Name Of The Medicinal Product

Lorazepam 1mg Tablets

2. Qualitative And Quantitative Composition

Lorazepam 1mg Tablets contain 1mg of the active ingredient lorazepam.

Lorazepam (INN, BAN) is chemically defined as 7-chloro-5-(0-chlorphenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.

3. Pharmaceutical Form

Lorazepam 1mg Tablets are blue, capsule-shaped tablets, measuring approximately 4 x 8mm, plain on one face and 'gp' breakbar '19' on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

FOR SHORT TERM (2-4 weeks only) USE (adults only)

• Symptomatic relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress occurring alone or in association with insomnia or short-term psychometric, organic or psychotic illness.

AS PREMEDICATION (adults and children 5 years and above)

• Before operative dentistry and general surgery

NOT FOR USE

• Long term (i.e. longer than 4 weeks)

• For mild/moderate anxiety

• For insomnia or anxiety in children

4.2 Posology And Method Of Administration

Route of administration: oral

Treatment to be given

• Under close medical supervision

• At the lowest effective dose

• For the shortest possible duration (not exceeding 4 weeks)

Doses should be individualised

Extension of use should not take place without further clinical evaluation

Chronic use not recommended (little is known of the long term safety and efficacy; potential for dependence – see section 4.4

When treatment is started the patient should be informed that

• treatment will be of limited duration

• the dosage will be progressively decreased

• there is a possibility of rebound phenomena

Dosage:

Adults:

Anxiety: 1-4mg daily in divided doses.

Insomnia: 1-2mg before retiring

Premedication before operative dentistry or general surgery:

2-3mg the night before operation 2-4mg one to two hours before the procedure

Elderly:

The elderly may respond to lower doses (half normal adult dose or less)

Children (aged 5-13 years):

Premedication: 0.5-2.5mg at 0.05mg/kg to the nearest 0.5mg according to weight, not less than one hour before operation.

Patients with Renal or Hepatic impairment:

Lower doses may be sufficient in these patients (See section 4.4). Use in patients with severe hepatic insufficiency is contraindicated. (See section 4.6)

4.3 Contraindications

• Hypersensitivity to benzodiazepines or to any of the other ingredients

• Acute pulmonary insufficiency: respiratory depression; sleep apnoea (risk of further respiratory depression)

• Obsessional states (inadequate evidence of safety and efficacy)

• Severe hepatic insufficiency (may precipitate encephalopathy)

• Planning a pregnancy (see section 4.6)

• Pregnancy (unless there are compelling reasons- see section 4.6)

• Myasthenia gravis;

Benzodiazepines should not be used alone in depression or anxiety with depression (may precipitate suicide)

4.4 Special Warnings And Precautions For Use

Patients should be advised that since their tolerance for alcohol and other CNS depressants will be diminished in the presence of Lorazepam, these substances should either be avoided or taken in reduced dosage.

Lorazepam is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients. Therefore, large quantities of Lorazepam should not be prescribed to these patients.

Pre-existing depression may emerge during benzodiazepine use.

The use of benzodiazepines may lead to physical and psychological dependence. The risk of dependence on Lorazepam is low when used at the recommended dose and duration, but increases with higher doses and longer-term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse, or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.

Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. (see 4.8 Undesirable effects). Therefore, the drug should always be discontinued gradually.

It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.

Abuse of benzodiazepines has been reported.

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.

Anxiety or insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.

Caution should be used in the treatment of patients with acute narrow-angle glaucoma.

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when Lorazepam is used as a premedicant. However, if Lorazepam is used for insomnia due to anxiety, patients should ensure that they will be able to have a period of uninterrupted sleep which is sufficient to allow dissipation of drug effect (e.g., 7-8 hours).

Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued (see Undesirable Effects).

Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended

Alcohol

Lorazepam should not be used together with alcohol (enhanced sedative effects; impaired ability to drive/operate machinery)

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate)

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation – see below for zidovudine

Take into account

Centrally acting drugs

Enhancement of the central depressive effect may occur if lorazepam is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.

Anti-epileptic drugs

Pharmacokinetic studies on potential interactions between benzodiazepines and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change have been reported.

Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment.

Side effects may be more evident with hydantoins or barbiturates

Valproate may inhibit the glucuronidation of lorazepam (increased serum levels: increased risk of drowsiness)

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence

Clozapine

Reports of marked sedation, excessive salivation, hypotension, ataxia, delirium and respiratory arrest when given concurrently with lorazepam.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle relaxants – baclofen and tizanidine

Compounds that affect hepatic enzymes (particularly cyctochrome P450)

• Inhibitors (e.g. cimetidine, isoniazid; erythyromycin; omeprazole; esomeprazole) reduce clearance and may potentiate the action of benzodiazepines. Itraconazole, ketoconazole and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiazapines. The effects of benzodiazapines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

• Inducers (e.g. rifampicin) may increase clearance of benzodiazepines

Antihypertensives, vasodilators and diuretics: Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics

Enhanced sedative effect with alpha-blockers or moxonidine.

Dopamionergics

Possible antagonism of the effect of levodopa

Antacids

Concurrent use may delay absorption of lorazepam

Zidovudine

Increased zidovudine clearance by lorazepam

Oestrogen-containing contraceptives

Possible inhibition of hepatic metabolism of lorazepam

Theophylline/aminophylline

Increases metabolism of lorazepam which possibly reduces the effect

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of lorazepam.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of lorazepam (possible increased sedation and amnesia).This interaction may be of little significance in healthy individuals, but it is not clear if other factors such as old age or liver cirrhosis increase the risk of adverse events with concurrent use.

4.6 Pregnancy And Lactation

Pregnancy: Benzodiazepines should not be used during pregnancy, especially during the first and last trimesters. Benzodiazepines may cause foetal damage when administered to pregnant women.

If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.

There is a possibility that infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence. Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnoea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.

Lactation: Lorazepam is excreted in small amounts in breast milk. Mothers who are breast-feeding should not take benzodiazepines. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscular function may occur and that, if affected, they should not drive or to use machines, or take part in other activities where this would put themselves or others at risk. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Concurrent medication may increase these effects (see section 4.5)

4.8 Undesirable Effects

Adverse reactions, when they occur, are usually observed at the beginning of therapy and generally decrease in severity or disappear with continued use or upon decreasing the dose.

Most frequently reported adverse reactions associated with benzodiazepines include daytime drowsiness, dizziness, muscle weakness, and ataxia.

Adverse reactions are listed by frequency:

Very common (

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, leucopenia, agranulocytosis, pancytopenia

Immune system disorders

Very rare: Hypersensitivity including anaphylaxis/anaphylactoid reactions

Endocrine disorders

Very rare: Inappropriate antidiuretic hormone secretion, hyponatraemia

Psychiatric disorders

Rare: Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, decreased orgasm.

Unknown: Dependence, Suicidal ideation/attempt

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour have been occasionally reported during use.

Nervous system

Very common: Daytime drowsiness, sedation

Common: Dizziness, ataxia

Rare: headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.

Very rare: Tremor, extrapyramidal reactions, Coma (see 4.9 Overdose)

Eye disorders

Rare: Visual disturbances (diplopia, blurred vision)

Vascular disorders

Rare: Hypotension (see 4.4 Special warnings and precautions)

Respiratory thoracic and mediastinal disorders:

Rare: Apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease. Respiratory depression (see 4.9 Overdose).

Gastrointestinal disorders

Rare: Nausea, constipation, salivation changes

Hepatobiliary disorders

Rare: Abnormal liver function test values (increases in bilirubin, transaminases, alkaline phosphatise), jaundice

Skin and subcutaneous tissue disorders

Rare: Rash, allergic dermatitis

Musculoskeletal disorders

Common: Muscle weakness

Reproductive system and breast disorders

Rare: Impotence

General disorders

Common: Asthenia, fatigue

Very rare: Hypothermia

Drug withdrawal symptoms (see 4.4 Special warnings and precautions)

Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of “rebound” phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

4.9 Overdose

In the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy. In more serious cases, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, coma, and very rarely, death.

If ingestion was recent, induced vomiting and/or gastric lavage should be undertaken followed by general supportive care, monitoring of vital signs and close observation of the patient. If there is no advantage in emptying the stomach, activated charcoal may be effective in reducing absorption. Hypotension, though unlikely, may be controlled with noradrenaline. Lorazepam is poorly dialysable.

The benzodiazepine antagonist, flumazenil may be useful in hospitalised patients for the management of benzodiazepine overdosage. Flumazenil product information should be consulted prior to use.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Lorazepam is a benzodiazepine with anxiolytic, sedative and hypnotic properties.

5.2 Pharmacokinetic Properties

Lorazepam is almost completely absorbed from the gastrointestinal tract and peak serum levels are reached in 2 hours. It is metabolised by a simple one-step process to a pharmacologically inert glucuronide. There are no major active metabolites. The elimination half-life is about 12 hours and there is minimal risk of excessive accumulation.

5.3 Preclinical Safety Data

Oesophageal dilation occurred in rats treated with lorazepam for more than one year at 6mg/kg/day.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose 72 mesh, Lactose powdered anhydrous, microcrystalline cellulose, polacrilin potassium, magnesium stearate, Colouring: E132.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store in a cool, dry place.

6.5 Nature And Contents Of Container

1. Blister packs of PVC backed by hard tempered aluminium foil: Pack sizes of 28, 30, 56, 60 or 100 tablets.

2. Opaque polypropylene Securitainers with opaque polythene caps: Pack sizes of 28, 30, 56, 60, 100, 500 or 1000 tablets.

3. Amber glass bottles with screw caps: Pack sizes of 28, 30, 56, 60, 100, 500 or 1000 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Holdings Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire RG14 1JN, UK

8. Marketing Authorisation Number(S)

PL 17225/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

1 September 1999

10. Date Of Revision Of The Text

09 December 2011

Lucentis 10 mg / ml solution for injection

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

One ml contains 10 mg ranibizumab. Each vial contains 2.3 mg of ranibizumab in 0.23 ml solution.

Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection

Sterile, clear, colourless to pale yellow aqueous solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Lucentis is indicated in adults for:

• the treatment of neovascular (wet) age-related macular degeneration (AMD) (see section 5.1).

• the treatment of visual impairment due to diabetic macular oedema (DME) (see section 5.1).

• the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) (see section 5.1).

4.2 Posology And Method Of Administration

Single-use vial for intravitreal use only.

Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections.

Treatment of wet AMD

In wet AMD, the recommended dose for Lucentis is 0.5 mg given monthly as a single intravitreal injection. This corresponds to an injection volume of 0.05 ml.

Treatment is given monthly and continued until maximum visual acuity is achieved i.e. the patient`s visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment.

Thereafter patients should be monitored monthly for visual acuity.

Treatment is resumed when monitoring indicates loss of visual acuity due to wet AMD. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.

Treatment of visual impairment due to either DME or macular oedema secondary to RVO (see also section 5.1)

The recommended dose for Lucentis is 0.5 mg given as a single intravitreal injection. This corresponds to an injection volume of 0.05 ml.

Treatment is given monthly and continued until maximum visual acuity is achieved i.e the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment. If there is no improvement in visual acuity over the course of the first three injections, continued treatment is not recommended.

Thereafter patients should be monitored monthly for visual acuity.

Treatment is resumed when monitoring indicates loss of visual acuity due to DME or to macular oedema secondary to RVO. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.

Lucentis and laser photocoagulation in DME and in macular oedema secondary to BRVO

There is some experience of Lucentis administered concomitantly with laser photocoagulation (see section 5.1). When given on the same day, Lucentis should be administered at least 30 minutes after laser photocoagulation. Lucentis can be administered in patients who have received previous laser photocoagulation.

Method of administration

As with all medicinal products for parenteral use, Lucentis should be inspected visually for particulate matter and discoloration prior to administration.

Before treatment, the patient should be instructed to self-administer antimicrobial drops (four times daily for 3 days before and following each injection).

The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis (if required). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.4). The periocular skin, eyelid and ocular surface should be disinfected and adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection.

For information on preparation of Lucentis, see section 6.6.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

Additional information on special populations

Hepatic impairment

Lucentis has not been studied in patients with hepatic impairment. However, no special considerations are needed in this population.

Renal impairment

Dose adjustment is not needed in patients with renal impairment (see section 5.2).

Paediatric population

Lucentis is not recommended for use in children and adolescents due to a lack of data on safety and efficacy in these sub-populations.

Elderly

No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DME.

Ethnicity

Experience with treatment is limited in groups other than Caucasians.

4.3 Contraindications

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

Patients with active or suspected ocular or periocular infections.

Patients with active severe intraocular inflammation.

4.4 Special Warnings And Precautions For Use

Treatment with Lucentis is for intravitreal injection only.

Intravitreous injections, including those with Lucentis, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering Lucentis. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of Lucentis. Sustained IOP increases have also been identified (see section 4.8). Both intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately.

The safety and efficacy of Lucentis therapy administered to both eyes concurrently have not been studied. If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events.

As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis. Since there is a potential for an increased systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient population cannot be excluded. Patients should also be instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation.

Lucentis should not be administered concurrently with other anti-VEGF (vascular endothelial growth factor) agents (systemic or ocular).

The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

• a decrease in best-corrected visual acuity (BCVA) of

• an intraocular pressure of

• a retinal break;

• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is

• performed or planned intraocular surgery within the previous or next 28 days.

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment. When initiating Lucentis therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

There is only limited experience in the treatment of subjects with DME due to type I diabetes. Lucentis has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with Lucentis in diabetic patients with an HbA1c over 12% and uncontrolled hypertension.

There are limited data on safety in the treatment of DME and macular oedema due to RVO patients with prior history of stroke or transient ischaemic attacks. Since there is a potential risk of arterial thromboembolic events following intravitreal use of VEGF (vascular endothelial growth factor) inhibitors caution should be exercised when treating such patients (see section 4.8).

There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischaemic visual function loss, treatment is not recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interaction studies have been performed.

For the adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in wet AMD, see section 5.1.

For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see sections 4.2 and 5.1.

4.6 Pregnancy And Lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should use effective contraception during treatment.

Pregnancy

For ranibizumab no clinical data on exposed pregnancies are available. Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child.

Breast-feeding

It is unknown whether Lucentis is excreted in human milk. Breast-feeding is not recommended during the use of Lucentis.

4.7 Effects On Ability To Drive And Use Machines

The Lucentis treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see section 4.8). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

4.8 Undesirable Effects

Wet AMD population

In wet AMD a total of 1,315 patients constituted the safety population in the three phase III studies with 24 months exposure to Lucentis and 440 patients were treated with the recommended dose of 0.5 mg.

Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).

Other serious ocular events observed among Lucentis-treated patients included intraocular inflammation and increased intraocular pressure (see section 4.4).

The adverse events listed below occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with Lucentis 0.5 mg than in those receiving control treatment (sham or verteporfin PDT) in the three controlled wet AMD phase III studies FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER). These were therefore considered potential adverse drug reactions. The safety data described below also include all adverse events (in at least 0.5 percentage points of patients) suspected to be at least potentially related to the injection procedure or medicinal product in the 440 patients of the combined 0.5 mg treatment groups in wet AMD.

DME population

The safety of Lucentis was studied in a one-year sham-controlled trial (RESOLVE) and in a one-year laser-controlled trial (RESTORE) conducted respectively in 102 and 235 ranibizumab-treated patients with visual impairment due to DME (see section 5.1). The event of urinary tract infection, in the common frequency category, met the adverse reaction criteria for the table below; otherwise ocular and non-ocular events in the RESOLVE and RESTORE trials were reported with a frequency and severity similar to those seen in the wet AMD trials.

RVO population

The safety of Lucentis was studied in two 12-month trials (BRAVO and CRUISE) conducted in 264 and 261 ranibizumab-treated patients with visual impairment due to macular oedema secondary to BRVO and CRVO, respectively (see section 5.1). Ocular and non-ocular events in the BRAVO and CRUISE trials were reported with a frequency and severity similar to those seen in the wet AMD trials.

The adverse events are listed by system organ class and frequency using the following convention: very common (

Infections and infestations
Very common	Nasopharyngitis
Common	Urinary tract infection*
Blood and lymphatic system disorders
Common	Anaemia
Immune system disorders
Common	Hypersensitivity
Psychiatric disorders
Common	Anxiety
Nervous system disorders
Very common	Headache
Eye disorders
Very common	Vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus.
Common	Retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia.
Uncommon	Blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesion, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation.
Respiratory, thoracic and mediastinal disorders
Common	Cough
Gastrointestinal disorders
Common	Nausea
Skin and subcutaneous tissue disorders
Common	Allergic reactions (rash, urticaria, pruritus, erythema)
Musculoskeletal and connective tissue disorders
Very common	Arthralgia
Investigations
Very common	Intraocular pressure increased

* observed only in DME population

Product-class-related adverse reactions: In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly increased in ranibizumab-treated patients. However, there was no consistent pattern among the different haemorrhages. There is a theoretical risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the Lucentis clinical trials in patients with AMD, DME and RVO and there were no major differences between the groups treated with ranibizumab compared to control.

4.9 Overdose

Cases of accidental overdose have been reported from the clinical studies in wet AMD and post-marketing data. Adverse reactions associated with these reported cases were intraocular pressure increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineovascularisation agents, ATC code: S01LA04

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁ and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression of the neovascular form of age-related macular degeneration or to visual impairment caused by either diabetic macular oedema or macular oedema secondary to RVO.

Treatment of wet AMD

In wet AMD, the clinical safety and efficacy of Lucentis have been assessed in three randomised, double-masked, sham- or active-controlled studies of 24 months duration in patients with neovascular AMD. A total of 1,323 patients (879 active and 444 control) were enrolled in these studies.

In study FVF2598g (MARINA), 716 patients with minimally classic or occult with no classic choroidal neovascularisation (CNV) received monthly intravitreal injections of Lucentis 0.3 mg (n=238) or 0.5 mg (n=240) or sham (n=238) injections.

In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of Lucentis 0.3 mg and sham PDT (n=140); 2) monthly intravitreal injections of Lucentis 0.5 mg and sham PDT (n=140); or 3) sham intravitreal injections and active verteporfin PDT (n=143). Sham or active verteporfin PDT was given with the initial Lucentis injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage.

Key outcome measures are summarised in Tables 1, 2 and Figure 1.

Table 1 Outcomes at Month 12 and Month 24 in study FVF2598g (MARINA)

Outcome measure	Month	Sham (n=238)	Lucentis 0.5 mg (n=240)
Loss of <15 letters in visual acuity (%)a (maintenance of vision, primary endpoint)	Month 12	62%	95%
Month 24	53%	90%
Gain of a	Month 12	5%	34%
Month 24	4%	33%
Mean change in visual acuity (letters) (SD)a	Month 12	-10.5 (16.6)	+7.2 (14.4)
Month 24	-14.9 (18.7)	+6.6 (16.5)
a p<0.01

Table 2 Outcomes at Month 12 and Month 24 in study FVF2587g (ANCHOR)

Outcome measure	Month	Verteporfin PDT (n=143)	Lucentis 0.5 mg (n=140)
Loss of <15 letters in visual acuity (%)a (maintenance of vision, primary endpoint)	Month 12	64%	96%
Month 24	66%	90%
Gain of a	Month 12	6%	40%
Month 24	6%	41%
Mean change in visual acuity (letters) (SD)a	Month 12	-9.5 (16.4)	+11.3 (14.6)
Month 24	-9.8 (17.6)	+10.7 (16.5)
a p<0.01

Figure 1 Mean change in visual acuity from baseline to Month 24 in study FVF2598g (MARINA) and study FVF2587g (ANCHOR)

Results from both trials indicated that continued ranibizumab treatment may also be of benefit in patients who lost

The use of Lucentis beyond 36 months has not been studied.

Study FVF3192g (PIER) was a randomised, double-masked, sham-controlled study designed to assess the safety and efficacy of Lucentis in 184 patients with all forms of neovascular AMD. Patients received Lucentis 0.3 mg (n=60) or 0.5 mg (n=61) intravitreal injections or sham (n=63) injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. From Month 14 of the study, sham-treated patients were allowed to cross over to receive ranibizumab and from Month 19, more frequent treatments were possible. Patients treated with Lucentis in PIER received a mean of 10 total treatments.

The primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline. After an initial increase in visual acuity (following monthly dosing), on average, patients' visual acuity declined with quarterly dosing, returning to baseline at Month 12 and this effect was maintained in most ranibizumab-treated patients (82%) at Month 24. Data from a limited number of subjects that crossed over to receive ranibizumab after more than a year of sham-treatment suggested that early initiation of treatment may be associated with a better preservation of visual acuity.

Data from an open label study (PROTECT) in 32 patients followed for 9 months in which the safety of same-day administration of verteporfin PDT and Lucentis 0.5 mg was evaluated showed that the incidence of intraocular inflammation following the initial treatment was 6.3% (2 of 32 patients).

In both the MARINA and ANCHOR studies, the improvement in visual acuity seen with Lucentis 0.5 mg at 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) scores. The differences between Lucentis 0.5 mg and the two control groups were assessed with p-values ranging from 0.009 to <0.0001.

Treatment of visual impairment due to DME

The efficacy and safety of Lucentis have been assessed in two randomised, double-masked, sham- or active controlled studies of 12 months duration in patients with visual impairment due to diabetic macular oedema. A total of 496 patients (336 active and 160 control) were enrolled in these studies, the majority had type II diabetes, 28 ranibizumab-treated patients had type I diabetes.

In the phase II study D2201 (RESOLVE), 151 patients were treated with ranibizumab (6 mg/ml, n=51, 10 mg/ml, n=51) or sham (n=49) by monthly intravitreal injections until pre-defined treatment stopping criteria were met. The initial ranibizumab dose (0.3 mg or 0.5 mg) could be doubled at any time during the study after the first injection. Laser photocoagulation was allowed as rescue treatment from Month 3 in both treatment arms. The study had two parts: an exploratory part (the first 42 patients analysed at Month 6) and a confirmatory part (the remaining 109 patients analysed at Month 12).

Key outcome measures from the confirmatory part of the study (2/3 of patients) are summarised in Table 3.

Table 3 Outcomes at Month 12 in study D2201 (RESOLVE) (overall study population)

Outcome measure	Ranibizumab pooled (n=102)	Sham (n=49)
Mean average change in BCVA from Month 1 to Month 12 compared to baselinea (letters) (SD) (primary endpoint)	+7.8 (7.72)	-0.1 (9.77)
Mean change in BCVA at Month 12a (letters) (SD)	+10.3 (9.14)	-1.4 (14.16)
Gain of a	60.8	18.4
Gain of	32.4	10.2
p-value	0.0043

^ap<0.0001

In the phase III study D2301 (RESTORE), 345 patients with visual impairment due to macular oedema were randomised to receive either intravitreal injection of ranibizumab 0.5 mg as monotherapy and sham laser photocoagulation (n=116), combined ranibizumab 0.5 mg and laser photocoagulation (n=118), or sham injection and laser photocoagulation (n=111). Treatment with ranibizumab was started with monthly intravitreal injections and continued until visual acuity was stable for at least three consecutive monthly assessments. The treatment was reinitiated when a reduction in BCVA due to DME progression was observed. Laser photocoagulation was administered at baseline on the same day, at least 30 minutes before injection of ranibizumab, and then as needed based on ETDRS criteria.

Key outcome measures are summarised in Table 4 and Figure 2.

Table 4 Outcomes at Month 12 in study D2301 (RESTORE)

Outcome measure compared to baseline	Ranibizumab 0.5 mg n=115	Ranibizumab 0.5 mg + Laser n=118	Laser   n=110
Mean average change in BCVA from Month 1 to Month 12a (±SD)	6.1 (6.4)	5.9 (7.9)	0.8 (8.6)
Gain of a (%)	37.4	43.2	15.5
Gain of	22.6	22.9	8.2
p-value	0.0032	0.0021

^ap<0.0001

Figure 2 Mean change in visual acuity from baseline over time in study D2301 (RESTORE)

BL=baseline; SE=standard error of mean

* Difference in least square means, p<0.0001/0.0004 based on two-sided stratified Cochran-Mantel-Haenszel test

The effect was consistent in most subgroups. However, subjects with a fairly good baseline BCVA (>73 letters) together with macular oedema with central retinal thickness of <300 μm did not appear to benefit from treatment with ranibizumab compared to laser photocoagulation.

The improvement in visual acuity seen with Lucentis 0.5 mg at 12 months was accompanied by patient-reported benefits with regards to most vision-related functions as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) scores. For other subscales of this questionnaire no treatment differences could be established. The difference between Lucentis 0.5 mg and the control group was assessed with p-values of 0.0137 (ranibizumab mono) and 0.0041 (ranibizumab+laser) for the VFQ-25 composite score.

In both studies, the improvement of vision was accompanied by a continuous decrease in the macular oedema as measured by central retinal thickness (CRT).

Treatment of visual impairment due to macular oedema secondary to RVO

The clinical safety and efficacy of Lucentis in patients with visual impairment due to macular oedema secondary to RVO have been assessed in the randomised, double-masked, controlled studies BRAVO and CRUISE that recruited subjects with BRVO (n=397) and CRVO (n=392), respectively. In both studies, subjects received either 0.3 mg or 0.5 mg intravitreal ranibizumab or sham injections. After 6 months, patients in the sham-control arms were crossed over to 0.5 mg ranibizumab. In BRAVO, laser photocoagulation as rescue was allowed in all arms from Month 3.

Key outcome measures from BRAVO and CRUISE are summarised in Tables 5 and 6 and Figures 3 and 4.

Table 5 Outcomes at Month 6 and 12 (BRAVO)

	Sham/Lucentis 0.5 mg (n=132)	Lucentis 0.5 mg (n=131)
Mean change in visual acuity at Month 6a (letters) (SD) (primary endpoint)	7.3 (13.0)	18.3 (13.2)
Mean change in BCVA at Month 12 (letters) (SD)	12.1 (14.4)	18.3 (14.6)
Gain of a (%)	28.8	61.1
Gain of	43.9	60.3
Proportion (%) receiving laser rescue over 12 months	61.4	34.4

^ap<0.0001

Figure 3 Mean change from baseline BCVA over time to Month 6 and Month 12 (BRAVO)

BL=baseline; SE=standard error of mean

Table 6 Outcomes at Month 6 and 12 (CRUISE)

	Sham/Lucentis 0.5 mg (n=130)	Lucentis 0.5 mg (n=130)
Mean change in visual acuity at Month 6a (letters) (SD) (primary endpoint)	0.8 (16.2)	14.9 (13.2)
Mean change in BCVA at Month 12 (letters) (SD)	7.3 (15.9)	13.9 (14.2)
Gain of a (%)	16.9	47.7
Gain of	33.1	50.8

^ap<0.0001

Figure 4 Mean change from baseline BCVA over time to Month 6 and Month 12 (CRUISE)

BL=baseline; SE=standard error of mean

In both studies, the improvement of vision was accompanied by a continuous and significant reduction in the macular oedema as measured by central retinal thickness.

In patients with BRVO (BRAVO and extension study HORIZON): After 2 years, subjects that were treated with sham in the first 6 months and subsequently crossed over to ranibizumab treatment had achieved comparable gains in VA (~15 letters) compared to subjects that were treated wit