Ibandronic acid Sandoz 50 mg Film Coated Tablets

1. Name Of The Medicinal Product

Ibandronic acid Sandoz 50 mg Film Coated 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 0.90 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablets.

White round biconvex tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Ibandronic acid Sandoz 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 Sandoz 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 Sandoz 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 Sandoz 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 Sandoz 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 Sandoz.

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

- Plain water is the only drink that should be taken with Ibandronic acid Sandoz. 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 Sandoz 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

See also section 4.4.

Ibandronic acid Sandoz 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 Sandoz 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 Ibandronic acid Sandoz 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 any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Ibandronic acid Sandoz 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 Sandoz.

Clinical studies have not shown any evidence of deterioration in renal function with long term Ibandronic acid Sandoz 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 Sandoz.

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.

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

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

In the pooled database from the 2 pivotal phase III trials (286 patients treated with Ibandronic acid Sandoz 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Ibandronic acid Sandoz 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 ReactionsReported Commonly and Greater than Placebo

Adverse Reaction	Placebo p. o. daily (n=277 patients) No. (%)	Ibandronic acid Sandoz 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 Sandoz 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 Sandoz. 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 Sandoz. 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: Bisphosphonate, 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 by⁴⁵ Ca 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 50 mg 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 Sandoz 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

Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinine clearance (CLcr). 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 Sandoz 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:

Povidone

Cellulose, microcrystalline

Crospovidone

Maize starch pregelatinised

Glycerol dibehenate

Silica, anhydrous colloidal

Tablet coat:

Lactose monohydrate

Macrogol 4000

Hypromellose (E464)

Titanium dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

Ibandronic acid Sandoz 50 mg film coated tablets are supplied in Polyamide/Al/PVC - Aluminum foil blister with 3, 6, 9, 28 or 84 tablets, packaged in a cardboard box.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sandoz Pharmaceuticals GmbH

Raiffeisenstraße 11, 83607 Holzkirchen

Germany

8. Marketing Authorisation Number(S)

EU/1/11/685/001

EU/1/11/685/002

EU/1/11/685/003

EU/1/11/685/004

EU/1/11/685/005

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first Authorisation: 27/07/2011

10. Date Of Revision Of The Text

27/07/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

Imodium Original 2mg Capsules

1. Name Of The Medicinal Product

Imodium Original 2 mg Capsules.

2. Qualitative And Quantitative Composition

Each capsule contains 2 mg Loperamide hydrochloride.

Excipient: lactose

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Capsule, hard.

Opaque green cap and grey body, hard gelatin capsule imprinted with 'Imodium' on cap and 'Janssen' on body containing white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults aged 18 years and over following initial diagnosis by a doctor.

4.2 Posology And Method Of Administration

The capsules should be taken with liquid.

ACUTE DIARRHOEA

Adults and children over 12:

2 capsules (4 mg) initially followed by 1 capsule (2 mg) after every loose stool.

The maximum daily dose should not exceed 6 capsules (12 mg).

SYMPTOMATIC TREATMENT OF ACUTE EPISODES OF DIARRHOEA ASSOCIATED WITH IRRITABLE BOWEL SYNDROME IN ADULTS AGED 18 YEARS AND OVER

Two capsules (4 mg) to be taken initially, followed by 1 capsule (2 mg) after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 capsules (12 mg).

USE IN ELDERLY

No dose adjustment is required for the elderly.

RENAL IMPAIRMENT

No dose adjustment is required for patients with renal impairment.

HEPATIC IMPAIRMENT

Although no pharmacokinetic data are available in patients with hepatic impairment, Imodium should be used with caution in such patients because of reduced first pass metabolism. (see 4.4 Special warnings and special precautions for use).

Method of administration

Oral use.

4.3 Contraindications

This medicine is contraindicated:

• in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

• in children less than 12 years of age.

• in patients with acute dysentery, which is characterised by blood in stools and high fever.

• in patients with acute ulcerative colitis.

• in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter.

• in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Imodium must not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Imodium must be discontinued promptly when ileus, constipation or abdominal distension develop.

4.4 Special Warnings And Precautions For Use

Treatment of diarrhoea with Imodium is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 24 hours, the administration of Imodium should be discontinued and patients should be advised to consult their doctor.

Patients with AIDS treated with this medicine for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, this medicine should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose leading to CNS toxicity.

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

If you are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by your doctor, you should return to him/her if the pattern of your symptoms changes. You should also return to your doctor if your episodes of diarrhoea continue for more than two weeks or there is a need for continued treatment of more than two weeks.

Special Warnings to be included on the leaflet:

Only take this medicine to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome if your doctor has previously diagnosed IBS.

If any of the following now apply, do not use the product without first consulting your doctor, even if you know you have IBS:

• If you are 40 years or over and it is some time since your last attack of IBS or the symptoms are different this time

• If you have recently passed blood from the bowel

• If you suffer from severe constipation

• If you are feeling sick or vomiting

• If you have lost your appetite or lost weight

• If you have difficulty or pain passing urine

• If you have a fever

• If you have recently travelled abroad

Consult your doctor if you develop new symptoms, or if your symptoms worsen, or your symptoms have not improved over two weeks.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages, is unknown.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e. subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

4.6 Pregnancy And Lactation

Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide HCl posseses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester.

Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breast-feeding.

Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects On Ability To Drive And Use Machines

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.

4.8 Undesirable Effects

Adults and children aged

The safety of loperamide HCl was evaluated in 2755 adults and children aged

The most commonly reported (i.e.

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhoea) or post-marketing experience.

The frequency categories use the following convention: very common (

Table 1: Adverse Drug Reactions

System Organ Class	Indication
Common	Uncommon	Rare
Immune System Disorders			Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona
Nervous System Disorders	Headache	Dizziness Somnolencea	Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya
Eye Disorders			Miosisa
Gastrointestinal Disorders	Constipation Nausea Flatulence	Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa	Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension
Skin and Subcutaneous Tissue Disorders		Rash	Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa
Renal and Urinary Disorders			Urinary retentiona
General Disorders and Administration Site Conditions			Fatiguea
a: Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (acute and chronic), including trials in children b: See section 4.4 Special Warnings and Special Precautions for use.

4.9 Overdose

Symptoms:

In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia and respiratory depression), constipation, urinary retention and ileus may occur. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects.

Treatment:

If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antipropulsives: ATC code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic Properties

The half-life of loperamide in man is 10.8 hours with a range of 9-14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize starch

Talc

Magnesium stearate (E572)

Capsule cap:

Titanium dioxide (E171)

Yellow ferric oxide (E172)

Indigo carmine (E132)

Gelatin

Capsule body:

Titanium dioxide (E171)

Black ferrous oxide (E172)

Indigo carmine (E132)

Erythrosine (E127)

Gelatin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister packs consisting of aluminium foil, hermetalu and polyvinyl chloride genotherm glass clear.

The blister strips are packed in cardboard cartons to contain 2, 4 or 6 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0310

9. Date Of First Authorisation/Renewal Of The Authorisation

15/12/2009

10. Date Of Revision Of The Text

27/07/2011

Ibuleve Speed Relief 5% Spray

1. Name Of The Medicinal Product

IBULEVE™ SPEED RELIEF 5% SPRAY

2. Qualitative And Quantitative Composition

Ibuprofen 5.0% w/w.

For excipients, see section List of excipients.

3. Pharmaceutical Form

Clear, colourless, fragrance-free, aqueous-alcoholic topical cutaneous spray solution.

4. Clinical Particulars

4.1 Therapeutic Indications

For fast local relief of backache, rheumatic pain, muscular aches, pains or swellings, such as sprains, strains and sports injuries.

4.2 Posology And Method Of Administration

Adults, including the elderly, and children over 12 years.

Holding the bottle upright or upside down, spray approximately 4 inches to 6 inches away from the skin. After every two to three sprays, gently massage the preparation into the skin, spreading the product over a wide area around the affected site. Apply 5 to 10 sprays (1 to 2 ml) depending on the extent and severity of the condition. This amount may be repeated three to four times daily, with individual doses administered at least 4 hours apart. Patients should not apply more than 40 sprays (8 ml) in any 24 hour period.

Not to be used with occlusive dressings.

Hands should be washed after use, unless treating them.

Unless recommended by a doctor, advice should be sought about continued treatment if symptoms persist for more than 2 weeks.

Do not use on children under the age of 12 years of age except on the advice of a doctor.

4.3 Contraindications

Not to be used if allergic to any of the ingredients, or in cases of hypersensitivity to aspirin, ibuprofen or related painkillers (including when taken by mouth), especially where associated with a history of asthma, rhinitis or urticaria. Not to be used on broken or damaged skin.

4.4 Special Warnings And Precautions For Use

This product is flammable. Do not spray near flames, electric heaters or similar objects.

Seek medical advice if symptoms worsen or persist.

Oral NSAIDs, including ibuprofen, can sometimes be associated with renal impairment, aggravation of active peptic ulcers, and can induce allergic bronchial reactions in susceptible asthmatic patients. Although the systemic absorption of topically applied ibuprofen is less than for oral dosage forms, these complications can occur in rare cases. For these reasons, patients with an active peptic ulcer, a history of kidney problems, asthma or intolerance to aspirin or ibuprofen should seek medical advice before using Ibuleve Speed Relief Spray.

Keep away from the eyes and mucous membranes. For external use only.

The label will include statements to the following effect:

If symptoms persist, consult your doctor or pharmacist.

Do not use if sensitive to any of the ingredients, particularly if asthmatic, suffer from rhinitis or urticaria and have previously shown hypersensitivity to aspirin, ibuprofen or related painkillers.

Patients with asthma, an active peptic ulcer or a history of kidney problems should seek medical advice before use, as should patients already taking aspirin or other painkillers.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Concurrent aspirin, ibuprofen or other NSAIDs may result in an increased incidence of undesirable effects.

4.6 Pregnancy And Lactation

Not to be used during pregnancy or lactation. Although no teratogenic effects have been demonstrated, ibuprofen should be avoided during pregnancy. The onset of labour may be delayed, and the duration of labour increased. Ibuprofen appears in breast milk in very low concentrations, but is unlikely to affect breast fed infants adversely.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Very rarely, susceptible patients may experience the following side effects with ibuprofen, but these are extremely uncommon when ibuprofen is administered topically. If they occur, treatment should be discontinued:

Hypersensitivity: hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm, or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Renal: renal impairment can occur in patients with a history of kidney problems.

Gastrointestinal: side effects such as abdominal pain and dyspepsia have been reported.

4.9 Overdose

Any overdose with a topical presentation of ibuprofen is extremely unlikely. Symptoms of severe ibuprofen overdosage (e.g. following accidental oral ingestion) include headache, vomiting, drowsiness and hypotension. Correction of severe electrolyte abnormalities should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuleve Speed Relief Spray is a topical preparation which has anti-inflammatory and analgesic properties. It contains the active ingredient, ibuprofen, which exerts its effects directly in inflamed tissues underlying the site of application, mainly by inhibiting prostaglandin biosynthesis.

Because it is formulated in an evaporative aqueous/alcoholic solution, Ibuleve Speed Relief Spray also exerts a soothing and cooling effect when applied to the affected area.

5.2 Pharmacokinetic Properties

Specially formulated for external application, the active ingredient penetrates through the skin rapidly and extensively (approximately 25% of a finite dose within 48 hours), achieving high, therapeutically relevant local concentrations in underlying soft tissues, joints and synovial fluid, whilst producing plasma levels that are unlikely to be sufficient to cause any systemic side effects, other than in rare individuals who are hypersensitive to ibuprofen.

Furthermore, there do not appear to be any appreciable differences between the oral and topical routes of administration regarding metabolism or excretion of ibuprofen.

5.3 Preclinical Safety Data

Published information on subchronic toxicity studies confirms that topically applied ibuprofen is well tolerated both locally and by the gastro-intestinal tract. Any local erythema is only mild and no signs of mucosal lesions or ulcerogenic effects have been determined in the gastro-intestinal tract.

In the course of assessing mucosal tolerance, topical ibuprofen has been found to cause acute, but reversible, irritant reactions in the eyes and mucous membranes.

6. Pharmaceutical Particulars

6.1 List Of Excipients

IMS; Polyethylene Glycol 300; Cetomacrogol 1000; Purified Water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

35 ml plastic bottle incorporating a controlled dose spray pump dispenser and overcap.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK

8. Marketing Authorisation Number(S)

00173/0160.

9. Date Of First Authorisation/Renewal Of The Authorisation

11 August 2008.

10. Date Of Revision Of The Text

October 2010.

Imipramine Hydrochloride 25mg / 5ml Oral Solution

1. Name Of The Medicinal Product

Imipramine Hydrochloride 25mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Imipramine hydrochloride (N-(γ-dimethylaminopropyl)-iminodibenzyl hydrochloride) 25mg / 5ml in an oral solution formulation

Each 5ml of solution also contains;

Sorbitol (E420)	1500.0 mg
Methylhydroxy benzoate (E218)	6.85 mg
Propylhydroxy benzoate (E216)	0.57 mg

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Oral Solution

A clear colourless banana flavoured solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptoms of depressive illness. Relief of nocturnal enuresis in children.

4.2 Posology And Method Of Administration

Depression:

Adults: 1 x 25mg up to three times daily, increasing stepwise to 150-200mg. This should be reached by the end of the first week and maintained until definite improvement has occurred. The subsequent maintenance dose should be individually determined by gradually reducing the dosage, usually to about 50-100mg daily.

In patients in hospital, i.e. severe cases, the dose may be increased to 100mg three times daily until a distinct improvement is seen. Again the subsequent maintenance dose should be determined individually by reducing the dosage, usually to about 100mg daily.

Elderly patients: Patients over 60 years of age may respond to lower doses of Imipramine Hydrochloride than those recommended above. Treatment should be initiated with 10mg daily, gradually increasing to 30-50mg daily. The optimum dose should be reached after about 10 days and then continued until the end of treatment.

Nocturnal Enuresis in Children: Not for use in children under 6 years.

6 - 7 years (weight 20-25kg or 44-55lbs) 25mg

8 - 11 years (weight 25-35kg or 55-77lbs) 25-50mg

Over 11 years (weight 35-54kg or 77-119lbs) 50-75mg

A daily dose of 2.5mg/kg should not be exceeded in children. The dose should be taken just before bedtime. The maximum period of treatment should not exceed three months and withdrawal should be gradual. Should a relapse occur, a further course of treatment should not be started until a full physical examination has been made.

4.3 Contraindications

Known hypersensitivity to imipramine, any of the excipients or cross-sensitivity to other tricyclic antidepressants of the dibenzazepine group. Recent myocardial infarction. Any degree of heart block or other cardiac arrhythmias, mania, severe liver disease, narrow angle glaucoma. Infants and children under 6 years old. Retention of urine. Concurrent use in patients receiving, or within 3 weeks of cessation of therapy with, monoamine oxidase inhibitors. Concomitant treatment with selective, reversible MAO-A inhibitors such as moclobemide, is also contra-indicated.

4.4 Special Warnings And Precautions For Use

Warnings

As improvement in depression may not occur for the first two to four weeks' treatment, patients should be closely monitored during this period.

Precautions

Tricyclic antidepressants are known to lower the convulsion threshold and Imipramine Hydrochloride should therefore be used with extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines). It appears that the occurrence of seizures is dose dependent.

Concomitant treatment of Imipramine Hydrochloride and electroconvulsive therapy should only be resorted to under careful supervision.

Caution is called for when giving tricyclic antidepressants to patients with severe renal disease.

Caution is called for when giving tricyclic antidepressants to patients with tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.

Many patients with panic disorders experience intensified anxiety symptoms at the start of the treatment with antidepressants. This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.

Caution is indicated in patients with hyperthyroidism or during concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects may occur.

Before initiating treatment it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure.

Although changes in the white blood cell count have been reported with imipramine only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few months of therapy.

Periodic monitoring of hepatic enzymes levels is recommended in patients with liver disease. In elderly patients monitoring of cardiac function is indicated.

Because of its anticholinergic properties, imipramine should be used with caution in patients with a history of increased intra-ocular pressure, narrow angle glaucoma, or urinary retention (e.g. diseases of the prostate).

Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in the elderly and bedridden patients.

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Imipramine hydrochloride. Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension (see interactions).

An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental check-ups are therefore advisable during long-term treatment.

Decreased lacrimation and accumulation of mucoid secretions due to anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

Risk of suicide is inherent to severe depression and may persist until significant remission occurs. Patients posing a high suicide risk require close supervision.

Imipramine may cause anxiety, feelings of unrest, and hyperexcitation in agitated patients and patients with accompanying schizophrenic symptoms.

Activation of psychosis has occasionally been observed in schizophrenic patients receiving tricyclic antidepressants. Hypomanic or manic episodes have also been reported during a depressive phase in patients with cyclic affective disorders receiving treatment with a tricyclic antidepressant. In such cases it may be necessary to reduce the dosage of Imipramine hydrochloride or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Imipramine hydrochloride may be resumed if required.

In predisposed and elderly patients, Imipramine hydrochloride may, particularly at night, provoke pharmacognic (delirious) psychoses, which disappear without treatment within a few days of withdrawing the drug. Agitation, confusion and postural hypotension may occur. Abrupt withdrawal should be avoided because of possible adverse reactions (see side effects).

Behavioural changes may occur in children receiving Imipramine hydrochloride for treatment of nocturnal enuresis.

Imipramine hydrochloride contains sorbitol so may be unsuitable for patients with hereditary fructose intolerance.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

MAO inhibitors: Do not give Imipramine hydrochloride for at least 3 weeks after discontinuation of treatment with MAO inhibitors (there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with Imipramine hydrochloride. In both instances Imipramine hydrochloride or the MAO inhibitors should initially be given in small, gradually increasing doses and its effects monitored. There is evidence to suggest that tricyclic antidepressants may be given as little as 24 hours after a reversible MAO inhibitor such as moclobemide, but the 3 week wash-out period must be observed if the MAO inhibitor is given after a tricyclic antidepressant has been used.

Selective serotonin reuptake inhibitors: Co-medication may lead to additive effects on the serotonergic system. Fluvoxetine and fluvoxamine may also increase plasma concentrations of imipramine, with corresponding adverse effects, resulting in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures.

CNS depressants: Tricyclic antidepressants may also increase the effects of alcohol and central depressant drugs (e.g. barbiturates, benzodiazepines or general anaesthetics).

Alprazolam and disulfiram: It may be necessary to reduce the dosage of imipramine if it is administered concomitantly with aprazolam or disulfiram.

Neuroleptics: Co-medication may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

Adrenergic neurone blockers: Imipramine may diminish or abolish the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine and alpha-methylodopa. Patients requiring co-medication for hypertension should therefore be given antihypertensives of a different type (e.g. diuretics, vasodilators, or beta blockers).

Anticoagulants: Tricyclic antidepressants may potentiate the anti-coagulant effect of coumarin drugs by inhibiting hepatic metabolism of these anticoagulants. Careful monitoring of plasma prothrombin is therefore advised.

Anticholinergic agents: Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.

Sympathomimetic drugs: Imipramine may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline phenylephrine, phenylpropanolamine (e.g. as contained in local anaesthetic preparations and nasal decongestants)

Quinidine: Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type.

Liver enzyme inducers: Drugs that activate the hepatic mono-oxygenase enzyme system (e.g. barbiturates, carbamazepine, phenytoin, nicotine, and oral contraceptives) may accelerate the metabolism and lower plasma concentrations of imipramine, resulting in decreased efficacy. Plasma levels of phenytoin and carbamazepine may increase, with corresponding adverse effects. It may be necessary to adjust the dosage of these drugs.

Cimetidine, methylphenidate, terbinafine, amfebutamone: These drugs may increase the plasma concentrations of tricyclic antidepressants, whose dosage should therefore b reduced.

Estrogens: There is evidence that estrogens can sometimes paradoxically reduce the effects of imipramine yet at the same time cause imipramine toxicity.

4.6 Pregnancy And Lactation

Use During Pregnancy and Lactation: There is no evidence of the safety of the drug in human pregnancy. There have been isolated reports of a possible connection between the use of tricyclic antidepressants and adverse effects (developmental disorders) on the foetus; treatment with Imipramine Hydrochloride should be avoided during pregnancy, unless the anticipated benefits justify the potential risk to the foetus.

Neonates whose mothers had taken imipramine up until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. Imipramine Hydrochloride should if possible be gradually withdrawn at least 7 weeks before the calculated date of confinement.

The active substance of Imipramine hydrochloride, imipramine, and its metabolites, desmethylimipramine, pass into the breast milk in small quantities. Imipramine hydrochloride should be gradually withdrawn or the mother advised to cease breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Patients receiving Imipramine Hydrochloride should be warned that blurred vision, drowsiness and other CNS symptoms (see Side Effects) may occur, in which case they should not drive, operate machinery, or do anything which may require alertness or quick actions. Patients should also be warned that alcohol or other drugs may potentiate these effects, (see Interaction).

4.8 Undesirable Effects

If severe neurological or psychiatric reactions occur, Imipramine hydrochloride should be withdrawn. Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.

The following side effects, although not necessarily observed with imipramine, have occurred with tricylic antidepressants.

(The following frequency estimates are used: frequently> 10%, occasionally>1-10%, rarely>0.001-1%, isolated cases <0.001%)

Central Nervous System

Psychiatric Effects:

Occasionally: fatigue, drowsiness, restlessness, delirium, confusion, disorientation and hallucination (particularly in geriatric patients and those suffering from Parkinson's disease) increased anxiety, agitation, sleep disturbances, swings from depression to hypomania or mania.

Rarely: activation of psychotic symptoms

Isolated cases: aggressiveness

Neurological Effects:

Frequently: tremor

Occasionally: paraestesiae, headache, dizziness.

Rarely: epileptic seizures.

Isolated cases of EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorder, drug fever.

Cardiovascular System:

Frequently: sinus tachycardia and clinically irrelevant ECG changes (T and ST changes) in patients of normal cardiac status, postural hypotension.

Occasionally: arrhythmias, conduction disorders (widening of QRS complex and PR interval, bundle-branch block), palpitations.

Isolated cases of increased blood pressure, cardiac decompensation, peripheral vasospastic reactions.

Anticholinergic Effects:

Frequently: dry mouth, sweating, constipation, disorders of visual accommodation, blurred vision, hot flushes.

Occasionally: disturbances of micturition.

Isolated cases of mydriasis, glaucoma, paralytic ileus.

Gastro-Intestinal Tract:

Occasionally: nausea, vomiting, anorexia.

Isolated cases of stomatitis, tongue lesions, abdominal disorders

Hepatic Effect:

Occasionally: elevated transaminases

Isolated cases of hepatitis with or without jaundice.

Skin:

Occasionally: allergic skin reactions (skin rash, urticaria)

Isolated cases of oedema (local or generalised), photosensitivity, hyperpigmentation, pruritus, petechiae, hair loss.

Endocrine System and Metabolism:

Frequently: weight gain

Occasionally: disturbances of libido, impotency or abnormal ejaculation.

Isolated cases of enlarged mammary glands, galactorrhoea, SIADH (syndrome of inappropriate antidiuretic hormone secretion), increase or decrease in blood sugar, weight loss.

Hypersensitivity:

Isolated cases of allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.

Blood:

Isolated cases of eosinophilia, leucopenia, agranulocytosis, thrombocytopenia and purpura.

Sense organs:

Tinnitus

Miscellaneous:

Occasional withdrawal symptoms following abrupt discontinuation of treatment: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness and anxiety. Contains 1.5g of sorbitol per 5ml spoonful so may cause stomach upset and diarrhoea, particularly at high doses.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

4.9 Overdose

The signs and symptoms of overdose with imipramine are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main complications. In children, accidental ingestion of any amount should be regarded as serious and potentially fatal.

Signs and Symptoms: Symptoms generally appear within 4 hours of ingestion and reach a maximum severity after 24 hours. Owing to delayed absorption (increased anticholinergic effect due to overdose), long half-life and enterohepatic recycling of the drug, the patient may be at risk for up to 4-6 days.

The following may be encountered:

Central nervous system: drowsiness stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity, athetoid and choreiform movements, convulsions.

Cardiovascular System: Hypotension, tachycardia, arrhythmia, conduction disorders, heart failure; in very rare cases, cardiac arrest.

In addition, respiratory depression, cyanosis, shock, vomiting, fever, hydriasis, sweating and oliguria or anuria may occur.

Treatment: There is no specific antidote and treatment is essentially symptomatic and supportive. Anyone suspected of receiving an overdose of imipramine, particularly children, should be admitted to hospital and kept under close surveillance for at least 72 hours.

Perform gastric lavage or induce vomiting as soon as possible if the patient is fully conscious. If the patient has impaired consciousness, secure the airway with a cuffed endotracheal tube before beginning lavage, and do not induce vomiting. These measures are recommended for up to 12 hours or even longer after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help reduce drug absorption.

Treatment of symptoms is based on modern methods of intensive care, with continuous monitoring of cardiac function, blood gases and electrolytes, and if necessary emergency measures such as:

• anticonvulsive therapy,

• artificial respiration,

• insertion of a temporary cardiac pacemaker,

• plasma expander, dopamine or dobutamine administered by intravenous drip,

• resuscitation.

Since it has been reported that physostigmine may cause severe bradycardia, asystole and seizures, its use is not recommended in cases of overdosage with imipramine. Haemodialysis or peritoneal dialysis are ineffective because of the low plasma concentrations of imipramine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tricyclic antidepressant. Noradrenaline (NA) and serotonin (5HT) re-uptake inhibitor. ATC Code N06A A02

Imipramine is a tricyclic antidepressant and has several pharmacological actions including alpha-adrenolytic, anti-histaminic, anticholinergic and 5HT-receptor blocking properties. However, the main therapeutic activity is believed to be inhibition of the neuronal re-uptake of noradrenaline and 5HT. Imipramine is a so-called 'mixed' re-uptake blocker, i.e. it inhibits the reuptake of NA and 5HT to about the same extent.

5.2 Pharmacokinetic Properties

Absorption: Imipramine is absorbed quickly and completely following oral administration. The intake of food has no effect on its absorption and bioavailability. During its first passage through the liver, orally administered imipramine becomes partly converted to desmethylimipramine, a metabolite which also exhibits antidepressant activity.

During oral administration of 50mg 3 times daily for 10 days, the mean steady-state plasma concentrations of imipramine and desmethylimipramine were 33-85ng/ml and 43-109ng/ml respectively. Owing to lower clearance in the plasma, resulting in increased systemic availability, elderly patients require lower doses of imipramine than patients in intermediate age groups. Renal impairment is not expected to have any influence on the kinetics of unchanged imipramine and its desmethyl metabolite since both are excreted only in small amounts by the kidneys.

Distribution: About 86% of imipramine binds to plasma proteins. Concentrations of imipramine in the cerebrospinal fluid and the plasma are highly correlated. The mean distribution volume is about 21 L/kg.

Imipramine and its metabolite desmethylimipramine both pass into breast milk in concentrations similar to those found in the plasma.

Biotransformation: Imipramine is extensively metabolised in the liver, It is cleared mainly by demethylation and to a lesser extent by hydroxylation. Both metabolic pathways are under genetic control.

Elimination: Imipramine is eliminated from the blood with a mean half-life of about 19 hours. About 80% is excreted in the urine and about 20% in the faeces, mainly in the form of inactive metabolites. Urinary excretion of unchanged imipramine and of the active metabolite desmethylimipramine is about 5% and 6% respectively. Only small quantities of these are excreted in the faeces.

Characteristics in patients: Owing to reduced metabolic clearance, plasma concentrations of imipramine are higher in elderly patients than in younger patients.

In children the mean clearance and elimination half-life does not differ significantly from adult controls but the between patient variability is high.

In patients with severe renal impairment, no change occurs in renal excretion of imipramine and its biologically active unconjugated metabolites. However, steady-state plasma concentrations of the conjugated metabolites which are considered to be biologically inactive, are elevated. The clinical significance of this finding is not known.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Betacyclodextrin (E459)

Sorbitol (E420)

Sodium saccharin (E954)

Hydroxyethylcellulose

Methyl paraben (E218)

Propyl paraben (E216)

Propylene glycol (E1520)

Banana flavour (containing nature identical flavouring substances and mono-propylene glycol as carrier)

Purified water.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years unopened.

30 days once opened.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container tightly closed.

6.5 Nature And Contents Of Container

Imipramine hydrochloride is supplied in 150 ml round Type III amber glass bottles with a white plastic child resistant clic-loc cap.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK

8. Marketing Authorisation Number(S)

PL 0427/0206

9. Date Of First Authorisation/Renewal Of The Authorisation

18^th May 2009

10. Date Of Revision Of The Text

26/07/2010

Intratect

INTRATECT 50 g/l solution for infusion

Human normal immunoglobulin for intravenous administration

Read all of this leaflet carefully before you start using this medicine

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


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


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


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

In this leaflet:

1. What INTRATECT is and what it is used for

2. Before you use INTRATECT

3. How to use INTRATECT

4. Possible side effects

5. How to store INTRATECT

6. Further information

What Intratect Is And What It Is Used For

INTRATECT is an extract of human blood which contains antibodies (the body’s own defensive substances) to diseases, available in the form of an infusion solution. The solution is ready for infusion into a vein (a “drip”).

INTRATECT is immunoglobulin (antibodies) from blood donated by a broad spectrum of the population and is likely to contain antibodies to most common infectious diseases. Adequate doses of INTRATECT can restore normal values when blood levels of Immunoglobulin G are low.

INTRATECT is used in patients who do not have sufficient antibodies (replacement therapy) in cases of:

• Patients born with lack of antibodies (primary immunodeficiency syndromes) such as:
  
  
  • congenital agammaglobulinemia or hypogammaglobulinemia
  • common variable immunodeficiency
  • severe combined immunodeficiencies
  • Wiskott Aldrich syndrome


• Patients with blood diseases that cause recurrent infections and a lack of antibody production such as:
  
  
  • myeloma
  • chronic lymphocytic leukaemia with severe secondary hypogammaglobulinemia
  • children born with AIDS and frequent infections

INTRATECT is also used to treat inflammatory disorders (immunomodulation) such as:

• Guillain-Barré syndrome (a disease that damages the nerves in the whole body)


• Kawasaki disease (a disease in children which causes inflammations of several organs of the body and where the arteries in the heart become enlarged)


• Idiopathic thrombocytopenic purpura (ITP, where a patient has reduced blood platelets) when the patient will have surgery in the near future or is at risk of bleeding

INTRATECT is also used against infection after bone marrow transplantation.

Before You Use Intratect

You should not be given INTRATECT if you

• are allergic (hypersensitive) to human immunoglobulin or any of the other ingredients of INTRATECT (see list of ingredients in Section 6). An allergic reaction may include rash, itching, difficulty breathing or swelling of the face, lips, throat or tongue.


• have an immunoglobulin A deficiency, especially if you have antibodies against immunoglobulin A in your blood

Take special care with INTRATECT (and talk to your doctor) if you

• suffer from a condition with low antibody levels in your blood (hypo- or agammaglobulinemia)


• have not received this medicine before or if there has been a long interval (e.g. several weeks) since you last received it (you will need to be closely monitored during your infusion and for an hour after your infusion has stopped)


• have been given INTRATECT recently (you will need to be observed during the infusion and for at least 20 minutes after your infusion)


• have had a reaction to other antibodies (in rare cases you may be at risk of allergic reactions)


• have or have had a kidney disorder


• have received medicines that may harm your kidneys (if your kidney function worsens, you may need to stop treatment with INTRATECT)

Your doctor will take special care if you are overweight, elderly, diabetic, or if you suffer from high blood pressure, low blood volume (hypovolaemia), if your blood is thicker than normal (high blood viscosity), if you have been bed-ridden or immobile for some time (immobilisation) or if you have problems with your blood vessels (vascular diseases) or other risks for thrombotic events (blood clots).

Please note - reactions

You will be carefully observed during the infusion period with INTRATECT to make sure that you do not suffer a reaction. Your doctor will make sure that the rate at which INTRATECT is infused is suitable for you.

If you notice any of the following signs of a reaction, i.e. sudden wheeziness, difficulty in breathing, fast pulse, swelling of the eyelids, face, lips, throat or tongue, rash or itching (especially affecting your whole body) during the infusion of INTRATECT, tell your doctor immediately. The rate of infusion can be slowed or the infusion can be stopped altogether.

Information on transmission of infectious agents

INTRATECT is made from human plasma (the liquid part of blood). When medicines are made from human blood or plasma, it is important to prevent infections being passed on to patients. Blood donors are tested for viruses and infections. Manufacturers of these products also process the blood or plasma to inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are given, the possibility of passing on infection cannot be totally excluded.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus.

The measures taken may be of limited value against non-enveloped viruses such as hepatitis A virus and parvovirus B19.

Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in the product, are protective.

Taking other medicines

Please tell your doctor if you are taking or have recently taken any other medicines including medicines obtained without a prescription.

INTRATECT can reduce the effectiveness of some vaccines such as:

• measles


• rubella


• mumps


• chicken pox

You may have to wait up to 3 months before you can have some vaccines and up to a year before you can have a measles vaccine.

Effects on blood tests

INTRATECT can affect blood tests. If you have a blood test after receiving INTRATECT, please inform the person taking your blood or your doctor that you have received INTRATECT.

Pregnancy and breast-feeding

Ask your doctor for advice before taking any medicine.

Your doctor will decide if INTRATECT may be used during pregnancy and breast-feeding.

Driving and using machines

INTRATECT has no known effects on your ability to drive or use machines.

How To Use Intratect

INTRATECT is intended for intravenous administration (infusion into a vein). It is given to you by a doctor or nurse. The dose will depend on your condition and your body weight. Your doctor will know the right amount to give you.

At the beginning of your infusion you will receive INTRATECT at a slow rate. Your doctor may then gradually increase the infusion rate.

The infusion rate and its frequency is dependant on the reason you are being given INTRATECT.

For replacement therapy in patients with a weak immune system (immunodeficiency) and for children with AIDS, the infusion is given every 2 or 3-4 weeks.

To treat inflammatory disorders (immunomodulation) the infusion may be given as followed:

Idiopathic Thrombocytopenic Purpura:

for the treatment of an acute episode an infusion is given on day 1, which may be repeated once in 3 days.

Alternatively a lower dosage may be given daily for 2 to 5 days.

Guillain Barré syndrome: the infusion is given for 3 to 7 days.

Kawasaki disease: the infusion should be administered over 2 to 5 days or as a single dose.

For bone marrow transplantation to treat infection and prevent rejection, the infusion is given every week for up to 3 months. Where there is lack of antibody production, the infusion is given every month until there are normal levels of antibodies.

If you miss an infusion

INTRATECT will be given to you in hospital by a doctor or nurse so you are unlikely to miss an infusion. However, tell your doctor if you think you have missed an infusion.

If you receive more INTRATECT than you should

An overdose can lead to fluid overload and increased thickness of the blood, especially in elderly patients or patients with reduced kidney function. If you think you have been given too much INTRATECT, tell your doctor, who will decide if the infusion should be stopped and an alternative treatment given. If you have any further questions on the use of this product, ask your doctor or nurse.

Possible Side-Effects

Like all medicines, INTRATECT can have side-effects, although not everybody gets them.

If you notice any of the following effects, tell your doctor immediately:

• rash,


• itching,


• wheezing,


• difficulty in breathing,


• swelling of the eyelids, face, lips, throat or tongue,


• extremely low blood pressure, fast pulse

This can be an allergic or a serious allergic reaction (anaphylactic shock) or a hypersensitivity reaction.

Tell your doctor straight away if you notice any of the following very rare effects:

• severe chest pain or chest pressure (heart attack, cardiac infarct)


• weakness, paralysis or numbness on one side of the body, loss of vision in one or both eyes, speech difficulties (stroke)


• cough, chest pain, rapid breathing, rapid heart rate (pulmonary embolism)


• swelling, pain, redness of the leg (deep vein thrombosis)

Occasionally, the following may occur:

• chills


• headache


• fever


• vomiting


• feeling sick (nausea)


• joint pain


• low blood pressure


• mild lower back pain

Rarely, the following may occur:

• a sudden fall in blood pressure


• temporary meningitis (inflammation of the brain lining)


• decrease in the number of red blood cells due to a breakdown of these cells in the blood vessels (haemolytic anaemia)


• eczema-like symptoms (temporary skin reactions)


• an increase in the serum creatinine (a waste product) and/or sudden kidney failure

Other reported side effects:

• severe chest pain or chest pressure (angina pectoris) (very rare)


• shivering or trembling (rigors) (very rare)


• decreased blood pressure (very rare)


• back pain (very rare)


• difficulty in breathing (dyspnoe) (very rare)

If a side effect occurs, the infusion rate will be decreased or stopped.

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

How To Store Intratect

Keep out of the reach and sight of children.

Your pharmacist or doctor knows how to store INTRATECT.

It should be kept in the outer carton to protect it from light.

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

Further Information

What INTRATECT contains:

• The active substance of INTRATECT is human immunoglobulin for intravenous administration. INTRATECT contains 50 g/l human plasma proteins of which at least 96 % is immunoglobulin G (IgG). The IgG subclass distribution is approx. 57 % IgG1, 37 % IgG2, 3 % IgG3 and 3 % IgG4. The maximum immunoglobulin A (IgA) content is 2 mg/ml.


• The other ingredients are: glycine and water for injections.

What INTRATECT looks like and the contents of the pack:

INTRATECT is a solution for infusion. The solution is clear to faintly opalescent (milky colours like an opal) and colourless to pale yellow.

Pack containing 1 vial with 1 g in 20 ml of solution

Pack containing 1 vial with 2.5 g in 50 ml of solution

Pack containing 1 vial with 5 g in 100 ml of solution

Pack containing 1 vial with 10 g in 200 ml of solution

Marketing Authorisation Holder and Manufacturer:

Biotest Pharma GmbH

Landsteinerstrasse 5

63303 Dreieich

Germany

Tel.:+ 49 6103 801-0

Fax:+ 49 6103 801-150 and -727

e-mail:info@biotest.de

PL 04500/0005

This leaflet was approved in October 2008