Dovobet Ointment

1. Name Of The Medicinal Product

Dovobet 50 microgram/g + 0.5 mg/g ointment

2. Qualitative And Quantitative Composition

One gram of ointment contains 50 micrograms of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Ointment.

Off-white to yellow.

4. Clinical Particulars

4.1 Therapeutic Indications

Topical treatment of stable plaque psoriasis vulgaris amenable to topical therapy in adults.

4.2 Posology And Method Of Administration

Posology

Dovobet ointment should be applied to the affected area once daily.

The recommended treatment period is 4 weeks. There is experience with repeated courses of Dovobet up to 52 weeks. If it is necessary to continue or restart treatment after 4 weeks, treatment should be continued after medical review and under regular medical supervision.

When using calcipotriol containing medicinal products, the maximum daily dose should not exceed 15 g. The body surface area treated with calcipotriol containing medicinal products should not exceed 30 % (see section 4.4).

Special populations

Renal and hepatic impairment

The safety and efficacy of Dovobet ointment in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated.

Paediatric population

The safety and efficacy of Dovobet ointment in children below 18 years have not been established. No data are available.

Method of administration

Dovobet ointment should be applied to the affected area. In order to achieve optimal effect, it is not recommended to take a shower or bath immediately after application of Dovobet ointment.

4.3 Contraindications

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

Dovobet ointment is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the content of calcipotriol Dovobet ointment is contra-indicated in patients with known disorders of calcium metabolism.

Due to the content of corticosteroid Dovobet ointment is contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds, perianal and genital pruritus.

4.4 Special Warnings And Precautions For Use

Effects on endocrine system

Dovobet ointment contains a potent group III steroid and concurrent treatment with other steroids must be avoided. Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus may occur also during topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin and under occlusive dressings or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids (see section 4.8).

In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Dovobet gel (scalp application) and high doses of Dovobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment (see section 5.1).

Effects on calcium metabolism

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose (15 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed. Treatment of more than 30 % of the body surface should be avoided (see section 4.2).

Local adverse reactions

Skin of the face and genitals are very sensitive to corticosteroids. The medicinal product should not be used in these areas. The patient must be instructed in correct use of the medicinal product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.

Concomitant skin infections

When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be stopped.

Discontinuation of treatment

When treating psoriasis with topical corticosteroids there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.

Long-term use

With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid (see section 4.8).

Unevaluated uses

There is no experience for the use of Dovobet ointment in guttate psoriasis.

Concurrent treatment and UV exposure

There is no experience for the use of this medicinal product on the scalp. Dovobet ointment for body psoriasis lesions has been used in combination with Dovobet gel for scalp psoriasis lesions, but there is no experience of combination of Dovobet with other topical anti-psoriatic products at the same treatment area, other anti-psoriatic medicinal products administered systemically or with phototherapy.

During Dovobet ointment treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks (see section 5.3).

Dovobet ointment contains butylhydroxytoluene (E321). This may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Dovobet ointment in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Dovobet ointment should only be used when the potential benefit justifies the potential risk.

Breastfeeding

Betamethasone passes into breast milk but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion of calcipotriol in breast milk. Caution should be exercised when prescribing Dovobet ointment to women who breast feed. The patient should be instructed not to use Dovobet ointment on the breast when breast feeding.

Fertility

Studies in rats with oral doses of calcipotriol or betamethasone dipropionate demonstrated no impairment of male and female fertility.

4.7 Effects On Ability To Drive And Use Machines

Dovobet has no or negligible influence on the ability to drive and to use machines.

4.8 Undesirable Effects

The trial programme for Dovobet ointment has so far included more than 2,500 patients and has shown that approximately 10 % of patients can be expected to experience a non-serious undesirable effect.

These reactions are usually mild and cover mainly various skin reactions like rash, pruritus and burning sensation. Pustular psoriasis has been reported rarely. Rebound effect after end of treatment has been reported but the frequency of this is not known.

Based on data from clinical trials and postmarket use the following adverse reactions are listed for Dovobet ointment.

The adverse reactions are listed by MedDRA System Organ Class, and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, the adverse reactions are listed in order of decreasing seriousness.

The following terminologies have been used in order to classify the frequencies of adverse reactions:

Very common
Common
Uncommon
Rare
Very rare	<1/10,000
Not known (cannot be estimated from the available data)

Skin and subcutaneous tissue disorders
Common	Pruritus Rash Burning sensation of skin
Uncommon	Exacerbation of psoriasis Skin pain or irritation Dermatitis Erythema Folliculitis Application site pigmentation changes
Rare	Pustular psoriasis
General disorders and administration site conditions
Not known	Rebound effect - included in section 4.4

The following adverse reactions are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema.

Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see section 4.4).

Betamethasone (as dipropionate)

Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis there may be a risk of generalised pustular psoriasis.

Systemic reactions due to topical use of corticosteroids are rare in adults, however they can be severe. Adrenocortical suppression, cataract, infections, impact on the metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur, especially after long term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long term treatment (see section 4.4).

4.9 Overdose

Use above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued.

Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal functions resulting in secondary adrenal insufficiency which is usually reversible. In such cases symptomatic treatment is indicated.

In case of chronic toxicity the corticosteroid treatment must be discontinued gradually.

It has been reported that due to misuse one patient with extensive erythrodermic psoriasis treated with 240 g of Dovobet ointment weekly (corresponding to a daily dose of approximately 34 g) for 5 months (maximum recommended dose 15 g daily) developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations. ATC Code: D05AX52

Calcipotriol is a vitamin D analogue. In vitro data suggests that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing the underlying condition. Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear.

A safety study in 634 psoriasis patients has investigated repeated courses of Dovobet ointment used once daily as required, either alone or alternating with Dovonex, for up to 52 weeks, compared with Dovonex used alone for 48 weeks after an initial course of Dovobet ointment. Adverse drug reactions were reported by 21.7 % of the patients in the Dovobet ointment group, 29.6 % in the Dovobet ointment/Dovonex alternating group and 37.9 % in the Dovonex group. The adverse drug reactions that were reported by more than 2 % of the patients in the Dovobet ointment group were pruritus (5.8 %) and psoriasis (5.3 %). Adverse events of concern possibly related to long-term corticosteroid use (e.g. skin atrophy, folliculitis, depigmentation, furuncle and purpura) were reported by 4.8 % of the patients in the Dovobet ointment group, 2.8 % in the Dovobet ointment/Dovonex alternating group and 2.9 % in the Dovonex group.

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Dovobet gel and Dovobet ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6 %) after 4 weeks of treatment and in 2 of 11 patients (18.2 %) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients. With regard to HPA suppression, therefore, this study shows some evidence that very high doses of Dovobet gel and ointment may have a weak effect on the HPA axis.

5.2 Pharmacokinetic Properties

Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet ointment is less than 1 % of the dose (2.5 g) when applied to normal skin (625 cm²) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Absorption through damaged skin is approx. 24 %.

Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised. Protein binding is approx. 64 %. Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation of a depot in the skin elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in the kidneys to glucuronide and sulphate esters. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate, respectively, showed that the kidney and liver had the highest level of radioactivity.

Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Dovobet gel and Dovobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.

5.3 Preclinical Safety Data

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.

A dermal carcinogenicity study with calcipotriol in mice revealed no special hazard to humans.

Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce skin tumours.

No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Liquid paraffin

Polyoxypropylene-15 stearyl ether

All-rac-α-tocopherol

White soft paraffin

Butylhydroxytoluene (E321)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

After first opening: 1 year.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium/epoxyphenol tubes with polyethylene screw cap.

Tube sizes: 3 (sample), 15, 30, 60, 100 and 120 g.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

LEO Pharmaceutical Products Ltd. A/S

Industriparken 55

DK-2750 Ballerup

Denmark

8. Marketing Authorisation Number(S)

PL 05293/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

15 March 2006

10. Date Of Revision Of The Text

April 2011

Ibandronic acid Avansor 50mg tablets

1. Name Of The Medicinal Product

Ibandronic acid Avansor 50 mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronic sodium monohydrate).

Excipients:

Each film-coated tablet contains 54 mg lactose monohydrate.For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White to off-white, oblong, biconvex film-coated tablets, 9 mm in length and debossed with “I9BE” on one side and on the other side with “50”.

4. Clinical Particulars

4.1 Therapeutic Indications

Ibandronic acid is indicated for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

4.2 Posology And Method Of Administration

Ibandronic acid therapy should only be initiated by physicians experienced in the treatment of cancer.

For oral use.

The recommended dose is one 50 mg film-coated tablet daily.

Ibandronic acid tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking ibandronic acid tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Plain water may be taken at any time during the course of ibandronic acid treatment.

- The tablets should be swallowed whole with a full glass of plain water (180 to 240 ml) while the patient is standing or sitting in an upright position.

- Patients should not lie down for 60 minutes after taking ibandronic acid.

- Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.

- Plain water is the only drink that should be taken with ibandronic acid. Please note that some mineral waters may have a higher concentration of calcium and therefore should not be used.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

Patients with renal impairment

No dosage adjustment is necessary for patients with mild renal impairment (CLcr

For patients with moderate renal impairment (CLcr

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly

No dose adjustment is necessary.

Children and adolescents

Ibandronic acid is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.

4.3 Contraindications

• Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

• Inability to stand or sit upright for at least 60 minutes

• Hypocalcaemia

• Hypersensitivity to ibandronic acid or to any of the excipients.

Ibandronic acid should not be used in children.

4.4 Special Warnings And Precautions For Use

Caution is indicated in patients with known hypersensitivity to other bisphosphonates.

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ibandronic acid therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue ibandronic acid and seek medical attention if they develop dysphagia, odynophagia, , retrosternal pain, or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Since NSAIDS are associated with gastrointestinal irritation, caution should be taken during concomitant oral medication with ibandronic acid.

Clinical studies have not shown any evidence of deterioration in renal function with long term ibandronic acid therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with ibandronic acid.

Ibandronic acid tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Drug-Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of ibandronic acid tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

Bioavailability was reduced by approximately 75% when ibandronic acid tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2).

Drug-Drug Interactions

When co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when ibandronic acid is administered with H2-antagonists or other drugs that increase gastric pH.

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, ibandronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

4.6 Pregnancy And Lactation

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, ibandronic acid should not be used during pregnancy.

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Ibandronic acid should not be used during lactation.

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 safety profile of ibandronic acid is derived from controlled clinical trials in the approved indication and after the oral administration of ibandronic acid at the recommended dose.

In the pooled database from the 2 pivotal phase III trials (286 patients treated with ibandronic acid 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to ibandronic acid was 27%.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Table 1 lists common adverse reactions from the pooled phase III trials. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo-treated patients are excluded.

Table 1: Adverse Reactions Reported Commonly and Greater than Placebo

Adverse reaction	Placebo p. o. daily (n=277 patients) No. (%)	Ibandronic acid 50 mg p.o. daily (n=286 patients) No. (%)
Metabolism and Nutrition Disorders Hypocalcaemia	14 (5.1)	27 (9.4)
Gastrointestinal Disorders Dyspepsia Nausea Abdominal Pain Oesophagitis	13 (4.7) 4 (1.4) 2 (0.7) 2 (0.7)	20 (7.0) 10 (3.5) 6 (2.1) 6 (2.1)
General Disorders Asthenia	2 (0.7)	4 (1.4)

Adverse drug reactions occurring at a frequency <1%:

The following list provides information on adverse drug reactions reported in study MF 4414 and MF 4434 occurring more frequently with ibandronic acid 50 mg than with placebo:

Uncommon:

Blood and Lymphatic System Disorders:	anaemia
Nervous System Disorders:	paraesthesia, dysgeusia (taste perversion)
Gastrointestinal Disorders:	haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth
Skin and Subcutaneous Tissue Disorders:	pruritus
Renal and Urinary Disorders:	azotaemia (uraemia)
General Disorders:	chest pain, influenza-like illness, malaise, pain
Investigations:	blood parathyroid hormone increased

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

4.9 Overdose

No case of overdose has been reported.

No specific information is available on the treatment of overdosage with ibandronic acid. However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind ibandronic acid. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Bisphosphonates, ATC Code: M05B A 06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with ibandronic acid 50 mg tablets was assessed in two randomized placebo controlled phase III trials with duration of 96 weeks.

Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg ibandronic acid (287 patients). The results from these trials are summarised below.

Primary Efficacy Endpoints

The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore, counted only once in any given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrated a significant advantage for ibandronic acid 50 mg p.o. over placebo in the reduction in SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE for ibandronic acid treated patients when compared with placebo (relative risk 0.62, p=0.003). Efficacy results are summarised in Table 2.

Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

	All Skeletal Related Events (SREs)
Placebo n=277	Ibandronic acid 50 mg, n=287	p-value
SMPR (per patient year)	1.15	0.99	P=0.041
SRE relative risk	-	0.62	P=0.003

Secondary Efficacy Endpoints

A statistically significant improvement in bone pain score was shown for ibandronic acid 50 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in Quality of Life and WHO performance status was significantly less in ibandronic acid treated patients compared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminal telopeptide released from Type I collagen) were significantly reduced in the ibandronic acid group compared to placebo. This reduction in urinary CTx levels was significantly correlated with the primary efficacy endpoint SMPR (Kendall-tau-b (p<0.001)). A tabular summary of the secondary efficacy results is presented in Table 3.

Table 3 Secondary Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

	Placebo n=277	Ibandronic acid n=287	p-value
Bone pain*	0.20	-0.10	p=0.001
Analgesic use*	0.85	0.60	p=0.019
Quality of life*	-26.8	-8.3	p=0.032
WHO performance score*	0.54	0.33	p=0.008
Urinary CTx**	10.95	-77.32	p=0.001

* Mean change from baseline to last assessment.

** Median change from baseline to last assessment

5.2 Pharmacokinetic Properties

Absorption

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration.

Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other than plain water). Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.

Bioavailability was reduced by approximately 75% when Ibandronic acid tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see Section 4.2).

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.

Metabolism

There is no evidence that ibandronic acid is metabolized in animals or humans.

Elimination

The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in Special Populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr >30 ml/min). Subjects with severe renal impairment (CLcr

Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor to take into consideration (see renal impairment section).

Children and adolescents

There are no data on the use of Ibandronic acid in patients less than 18 years old.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid in intravenously or orally treated rats and rabbits. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drugs (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Lactose Monohydrate

Crospovidone (E1202)

Cellulose, microcrystalline (E460)

Sylica, Colloidal Anhydrous (E551)

Sodium Stearyl Fumarate

Tablet coating

Poly (Vinyl Alcohol)

Macrogols/PEG 3350

Talc (E553b)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

OPA/Al/PVC:Al blisters in carton boxes containing 1, 28, 30, 84, 90 and 100 tablets

PVC/PVDC:Al blisters in carton boxes containing 1, 28, 30, 84, 90 and 100 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Avansor Pharma Oy

Tekniikantie 14

Espoo

02150

8. Marketing Authorisation Number(S)

PL 29834/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

23/11/2010

10. Date Of Revision Of The Text

23/11/2010

LEGAL CATEGORY

POM

Depo-Medrone 40mg / ml

1. Name Of The Medicinal Product

Depo-Medrone 40 mg/ml.

2. Qualitative And Quantitative Composition

Methylprednisolone Acetate BP 40 mg/ml.

3. Pharmaceutical Form

Sterile, aqueous suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Depo-Medrone may be used locally or systemically, particularly where oral therapy is not feasible.

Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional or into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see Contra-indications and Undesirable effects).

Intramuscular administration:

1. Rheumatic disorders

Rheumatoid arthritis

2. Collagen diseases/arteritis

Systemic lupus erythematosus

3. Dermatological diseases

Severe erythema multiforme (Stevens-Johnson syndrome)

4. Allergic states

Bronchial asthma

Severe seasonal and perennial allergic rhinitis

Drug hypersensitivity reactions

Angioneurotic oedema

5. Gastro

Ulcerative colitis

Crohn's disease

6. Respiratory diseases

Fulminating or disseminated tuberculosis (with appropriate antituberculous chemotherapy)

Aspiration of gastric contents

7. Miscellaneous

TB meningitis (with appropriate antituberculous chemotherapy)

Intra-articular administration:

Rheumatoid arthritis

Osteo-arthritis with an inflammatory component

Soft tissue administration (intrabursal, periarticular, into tendon sheath):

Synovitis not associated with infection

Epicondylitis

Tenosynovitis

Plantar fasciitis

Bursitis

Intralesional:

Keloids

Localized lichen planus

Localized lichen simplex

Granuloma annulare

Discoid lupus erythematosus

Alopecia areata

4.2 Posology And Method Of Administration

Depo-Medrone should not be mixed with any other suspending agent or solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever suspension and container permit. Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional and into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see Contra-indications and Undesirable effects).

Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Special warnings and special precautions for use).

Depo-Medrone vials are intended for single dose use only.

Intramuscular - for sustained systemic effect: Allergic conditions (severe seasonal and perennial allergic rhinitis, asthma, drug reactions), 80 - 120 mg (2 - 3 ml).

Dermatological conditions, 40 - 120 mg (1 - 3 ml).

Rheumatic disorders and collagen diseases (rheumatoid arthritis, SLE), 40 - 120 mg (1 - 3 ml) per week.

Dosage must be individualized and depends on the condition being treated and its severity.

Note: Depo-Medrone is not intended for the prophylaxis of severe seasonal and perennial allergic rhinitis or other seasonal allergies and should be administered only when symptoms are present.

The frequency of intramuscular injections should be determined by the duration of clinical response.

In the case of seasonal allergic rhinitis a single injection is frequently sufficient. If necessary, however, a second injection may be given after two to three weeks.

On average the effect of a single 2 ml (80 mg) injection may be expected to last approximately two weeks.

Intra-articular: Rheumatoid arthritis, osteo-arthritis. The dose of Depo-Medrone depends upon the size of the joint and the severity of the condition. Repeated injections, if needed, may be given at intervals of one to five or more weeks depending upon the degree of relief obtained from the initial injection. A suggested dosage guide is: large joint (knee, ankle, shoulder), 20 - 80 mg (0.5 - 2 ml); medium joint (elbow, wrist), 10 - 40 mg (0.25 - 1 ml); small joint (metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular), 4 - 10 mg (0.1 - 0.25 ml).

Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 4 - 30 mg (0.1 - 0.75 ml). In most cases, repeat injections are not needed.

Intralesional: Keloids, localised lichen planus, localized lichen simplex, granuloma annulare, alopecia areata, and discoid lupus erythematosus. For administration directly into the lesion for local effect in dermatological conditions, 20 - 60 mg (0.5 - 1.5 ml). For large lesions, the dose may be distributed by repeated local injections of 20 - 40 mg (0.5 - 1 ml). One to four injections are usually employed. Care should be taken to avoid injection of sufficient material to cause blanching, since this may be followed by a small slough.

Peri-articular: Epicondylitis. Infiltrate 4 - 30 mg (0.1 - 0.75 ml) into the affected area.

Into the tendon sheath: Tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 4 - 30 mg (0.1 - 0.75 ml). In recurrent or chronic conditions, repeat injections may be necessary.

Special precautions should be observed when administering Depo-Medrone. Intramuscular injections should be made deeply into the gluteal muscles. The usual technique of aspirating prior to injection should be employed to avoid intravascular administration. Doses recommended for intramuscular injection must not be administered superficially or subcutaneously.

Intra-articular injections should be made using precise, anatomical localisation into the synovial space of the joint involved. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal and hip joints. The spinal joints, unstable joints and those devoid of synovial space are not suitable. Treatment failures are most frequently the result of failure to enter the joint space. Intra-articular injections should be made with care as follows: ensure correct positioning of the needle into the synovial space and aspirate a few drops of joint fluid. The aspirating syringe should then be replaced by another containing Depo-Medrone. To ensure position of the needle, synovial fluid should be aspirated and the injection made. After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.

Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 per cent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis care should be taken to inject Depo-Medrone into the tendon sheath rather than into the substance of the tendon. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.

Children: Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient, than by age or size.

Elderly patients: When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Special warnings and special precautions for use).

4.3 Contraindications

Depo-medrone is contra-indicated where there is known hypersensitivity to components and in systemic infection unless specific anti-infective therapy is employed.

Due to its potential for neurotoxicity, Depo-Medrone must not be given by the intrathecal route. In addition, as the product is a suspension it must not be given by the intravenous route (see Undesirable effects).

4.4 Special Warnings And Precautions For Use

Warnings and Precautions:

1. A Patient Information Leaflet is provided in the pack by the manufacturer.

2. Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Posology and method of administration).

3. Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

4. Depo-Medrone vials are intended for single dose use only. Any multidose use of the product may lead to contamination.

5. Depo-Medrone is not recommended for epidural, intranasal, intra-ocular, or any other unapproved route of administration. See Undesirable effects section for details of side-effects reported from some non-recommended routes of administration.

6. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.

7. While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra

8. Intralesional doses should not be placed too superficially, particularly in easily visible sites in patients with deeply pigmented skins, since there have been rare reports of subcutaneous atrophy and depigmentation.

9. Systemic absorption of methylprednisolone occurs following intra

10. Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.

11. Following a single dose of Depo-Medrone, plasma cortisol levels are reduced and there is evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. This suppression lasts for a variable period of up to 4 weeks. The usual dynamic tests of HPA axis function can be used to diagnose evidence of impaired activity (e.g. Synacthen test).

12. Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.

• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).

• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.

• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.

• Patients repeatedly taking doses in the evening.

13. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

14. Because rare instances of anaphylactic reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.

15. Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

16. Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

17. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

18. The use of Depo-Medrone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

19. Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Undesirable effects).

20. The following precautions apply for parenteral corticosteroids: Following intra

Local injection of a steroid into a previously infected joint is to be avoided.

Corticosteroids should not be injected into unstable joints.

Sterile technique is necessary to prevent infections or contamination.

The slower rate of absorption by intramuscular administration should be recognised.

Special precautions:

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

1. Osteoporosis (post-menopausal females are particularly at risk).

2. Hypertension or congestive heart failure.

3. Existing or previous history of severe affective disorders (especially previous steroid psychosis).

4. Diabetes mellitus (or a family history of diabetes).

5. History of tuberculosis.

6. Glaucoma (or a family history of glaucoma).

7. Previous corticosteroid-induced myopathy.

8. Liver failure or cirrhosis.

9. Renal insufficiency.

10. Epilepsy.

11. Peptic ulceration.

12. Fresh intestinal anastomoses.

13. Predisposition to thrombophlebitis.

14. Abscess or other pyogenic infections.

15. Ulcerative colitis.

16. Diverticulitis.

17. Myasthenia gravis.

18. Ocular herpes simplex, for fear of corneal perforation.

19. Hypothyroidism.

20. Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Use in Children: Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.

2. Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

3. Drugs such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance.

4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

5. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

6. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.

7. Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular block.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Lactation

Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see Special warnings and special precautions for use).

PARENTERAL CORTICOSTEROID THERAPY - Anaphylactic reaction or allergic reactions, hypopigmentation or hyperpigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post injection flare (following intra-articular use), Charcot-like arthropathy, rare instances of blindness associated with intralesional therapy around the face and head.

GASTRO-INTESTINAL - Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of bowel.

Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS - Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Special warnings and special precautions for use).

MUSCULOSKELETAL - Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, aseptic necrosis, muscle weakness.

FLUID AND ELECTROLYTE DISTURBANCE - Sodium and water retention, potassium loss, hypertension, hypokalaemic alkalosis, congestive heart failure in susceptible patients.

DERMATOLOGICAL - Impaired healing, petechiae and ecchymosis, thin fragile skin, skin atrophy, bruising, striae, telangiectasia, acne.

ENDOCRINE/METABOLIC - Suppression of the hypothalamo-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance. Increased appetite.

NEUROPSYCHIATRIC

OPHTHALMIC - Increased intra-ocular pressure, glaucoma, papilloedema, cataracts with possible damage to the optic nerve, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease, exophthalmos.

GENERAL - Leucocytosis, hypersensitivity including anaphylaxis, thrombo-embolism, nausea, vertigo.

WITHDRAWAL SYMPTOMS - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see Special warnings and special precautions for use).

A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

CERTAIN SIDE-EFFECTS REPORTED WITH SOME NON-RECOMMENDED ROUTES OF ADMINISTRATION.

Intrathecal: Usual systemic corticoid adverse reactions, headache, meningismus, meningitis, paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, convulsions.

Extradural: Wound dehiscence, loss of sphincter control.

Intranasal: Permanent/temporary blindness, rhinitis.

Ophthalmic: (Subconjunctival) - Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.

Miscellaneous injection sites - Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.

4.9 Overdose

There is no clinical syndrome of acute overdosage with Depo-Medrone. Following overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further traumatic episode.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methylprednisolone acetate is a synthetic glucocorticoid. An aqueous suspension may be injected directly into joints and soft tissues in the treatment of rheumatoid arthritis, osteoarthritis, bursitis and similar inflammatory conditions. For prolonged systemic effect it may be administered intramuscularly.

5.2 Pharmacokinetic Properties

Methylprednisolone acetate is absorbed from joints in a few days, with peak serum levels being reached 2-12 hours after injection.

It is more slowly absorbed following deep intramuscular injection with plasma levels detected up to 17 days afterwards.

Methylprednisolone acetate is less soluble than methylprednisolone.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyethylene glycol, sodium chloride, myristyl-gamma-picolinium chloride and sterile water for injections.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Shelf-life of the medicinal product as packaged for sale: 60 months.

Depo-Medrone should not be mixed with any other fluid. Discard any remaining suspension after use.

6.4 Special Precautions For Storage

Depo-Medrone should be protected from freezing.

6.5 Nature And Contents Of Container

Type I flint glass vial with a butyl rubber plug and metal seal. Each vial contains 1 ml, 2ml, or 3 ml of Depo-Medrone 40 mg/ml.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pharmacia Ltd

Ramsgate Road

Sanwich

Kent CT13 9NJ

UK

8. Marketing Authorisation Number(S)

PL 0032/5038

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 7 March 1989.

Last renewal date: 5 September 1996

10. Date Of Revision Of The Text

October2009

Ref: DM5_0 UK

Pantoprazole 40 mg gastro-resistant tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Pantoprazole 40 mg gastro-resistant tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 40 mg pantoprazole

(as pantoprazole sodium sesquihydrate 45.16 mg)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

Elliptical, biconvex, dark yellow gastro-resistant tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and adolescents 12 years of age and above

• Reflux oesophagitis.

Adults

• Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

• Gastric and duodenal ulcer.

• Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

4.2 Posology And Method Of Administration

Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.

Recommended dose

Adults and adolescents 12 years of age and above

Reflux oesophagitis

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Adults

Eradication of H. pylori in combination with two appropriate antibiotics in H. pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination therapy should be achieved. Considerations should be given to official local guidance (e.g. national recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial agents. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori:

a) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 500 mg clarithromycin

b) twice daily one tablet Pantoprazole tablets

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

+ twice daily 250 - 500 mg clarithromycin

c) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

In combination therapy for eradication of H. pylori infection, the second Pantoprazole tablets tablet should be taken 1 hour before the evening meal. The combination therapy is implemented for 7 days in general and can be prolonged for a further 7 days to a total duration of up to two weeks. If, to ensure healing of the ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and gastric ulcers should be considered.

If combination therapy is not an option, e.g. if the patient has tested negative for H. pylori, the following dose guidelines apply for Pantoprazole tablets monotherapy:

Treatment of gastric ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of Pantoprazole tablets 40 mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.

Special populations

Children below 12 years of age

Pantoprazole tablets is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group.

Hepatic Impairment

A daily dose of 20 mg pantoprazole (1 tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment of these patients (see section 4.4).

Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment for these patients.

Elderly

No dose adjustment is necessary in elderly patients.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients

4.4 Special Warnings And Precautions For Use

Hepatic Impairment

In patients with severe liver impairment, particularly those on long-term use, liver enzymes should be monitored regularly during treatment with pantoprazole. In the case of a rise in liver enzymes, pantoprazole 40mg gastro-resistant tablets should be discontinued.

Combination therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with atazanavir

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended in combination with an increase in the dose of atazanavir to 400mg with 100mg of ritonavir. A pantoprazole dose of 20mg per day should not be exceeded.

Influence on vitamin B12 absorption

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

Long term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Gastrointestinal infections caused by bacteria

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

To date, there has been no experience with treatment in children.

Note:

Prior to treatment of gastric ulcer, the possibility of malignancy should be excluded as treatment with pantoprazole 40mg gastro-resistant tablets may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of pantoprazole on the absorption of other medicinal products

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended (see section 4.4).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants, monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Lactation

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with pantoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of pantoprazole therapy to women.

4.7 Effects On Ability To Drive And Use Machines

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

4.8 Undesirable Effects

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1 % of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:

very common (

common (

uncommon (

rare (

very rare (<1/10,000),

not known (cannot be estimated from the available data).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse

Reaction frequency and therefore they are mentioned with a “not known” frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency Organ system	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system			Thrombocytopenia Leukopenia;
Immune system disorders		Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutritional disorders		Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia
Psychiatric disorders	Sleep disorders	Depression (and all aggravations)	Disorientation (and all aggravations)	Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders	Headache; Dizziness
Eye disorders		Disturbances in vison/ blurred vision
Gastrointestinal Disorders	Diarrhoea; Nausea /vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort Flatulence
Hepatobiliary disorders	Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Skin and subcutaneous tissue disorders	Rash / exanthema / eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity
Musculoskeletal, connective tissue disorders		Arthralgia; Myalgia
Renal and urinary disorders				Interstitial nephritis
Reproductive system and breast disorders		Gynaecomastia
General disorders and administration site conditions	Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up to 240mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during longterm treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

5.2 Pharmacokinetic Properties

General pharmacokinetics

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 μg/ml are achieved, and these values remain constant after multiple administration.

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

The absolute bioavailability from the tablet was found to be about 77 %. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Distribution

Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg

Elimination

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80 %) for the metabolites of pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects

Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole.

No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed halflife (2 - 3 h), excretion is still rapid and thus accumulation does not occur.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects.

A slight increase in AUC and C_max in elderly volunteers compared with younger counterparts is also not clinically relevant.

Children

Following administration of single oral doses of 20 or 40 mg pantoprazole to children aged 5 - 16 years AUC and C_max were in the range of corresponding values in adults.

Following administration of single i.v. doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 - 16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent studies an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg.

Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Sodium carbonate anhydrous

Sodium starch glycolate, Type A

Methacrylic acid copolymer

Calcium stearate

Opadry white OY-D-7233 (hypromellose, titanium dioxide, talc, macrogol, sodium lauryl sulphate)

Kollicoat MAE 30 DP yellow (methacrylic acid-ethyl acrylate copolymer dispersion 30%, propylene glycol, yellow iron oxide, titanium dioxide, talc)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Pantoprazole 40mg gastro-resistant tablets are provided in aluminium/aluminium blister packs of 2, 7, 14, 15, 28, 30, 50, 56, 60, 84, 90, 100, 112, 140, 280, 500, or 700 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0299

9. Date Of First Authorisation/Renewal Of The Authorisation

29/04/2010

10. Date Of Revision Of The Text

20.10.2011