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

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.

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.

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

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.

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

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.

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.

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.

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

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 ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data)

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)

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.

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:

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

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

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.

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:

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.

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.

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

Not applicable

2 years

Do not store above 25°C.

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

Not applicable

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

United Kingdom

PL 16950/0173 - 0175

30 April 2009

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.