Doxorubicin Hydrochloride 2mg / ml solution for infusion (hameln)

1. Name Of The Medicinal Product

Doxorubicin Hydrochloride 2 mg/ml solution for infusion

2. Qualitative And Quantitative Composition

1ml contains 2 mg Doxorubicin hydrochloride.

Each 5ml vial contains a total content of Doxorubicin hydrochloride of 10 mg.

Each 10ml vial contains a total content of Doxorubicin hydrochloride of 20 mg.

Each 25ml vial contains a total content of Doxorubicin hydrochloride of 50 mg.

Each 75ml vial contains a total content of Doxorubicin hydrochloride of 150 mg.

Each 100ml vial contains a total content of Doxorubicin hydrochloride of 200 mg.

The product contains sodium chloride (3.5 mg sodium per 1 ml). For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for infusion

The product is a clear, red solution which is practically free of particles.

4. Clinical Particulars

4.1 Therapeutic Indications

Antimitotic and cytotoxic. Doxorubicin has been used with success to produce regression in a wide range of neoplastic conditions including acute leukaemia, lymphomas, soft-tissue and osteogenic sarcomas, paediatric malignancies and adult solid tumours, in particular of breast and lung. Doxorubicin can be used in the treatment of non-metastatic transitional cell carcinoma, carcinoma in situ and papillary tumours of the bladder, by intravesical administration.

Doxorubicin is frequently used in combination chemotherapy regimens with other cytostatic drugs.

4.2 Posology And Method Of Administration

4.2.1 For intravenous use

The solution is given via the tubing of a freely running intravenous infusion of sodium chloride 0.9 % or dextrose 5 % into a large vein using a Butterfly needle, taking 2 to 3 minutes over the injection. This technique minimises the risk of thrombosis or perivenous extravasation, which can lead to severe local cellulitis and necrosis.

Dosage is usually calculated on the basis of body surface area. On this basis, a dose of 60 - 75 mg/m² body surface area is recommended every three weeks when doxorubicin is used alone. If using the body weight to calculate the dose, dosages of 1.2 – 2.4 mg/kg are recommended. If it is used in combination with other antitumour agents with overlapping toxicity, such as high-dose i.v. cyclophosphamide or related anthracycline compounds such as daunorubicin, idarubicin and/or epirubicin, the dosage of doxorubicin should be reduced to 30 - 40 mg/m² every three weeks.

Dividing the dose over three successive days (20 - 25mg/m² or 0.4 - 0.8mg/kg on each day) gives greater effectiveness at the cost of higher toxicity. Administration of doxorubicin in a weekly regimen has been shown to be as effective as the 3² weekly, although objective responses have been seen at 6 – 12 mg/m². Weekly administration has been shown to be associated with reduced cardiotoxicity compared with a 3-weekly schedule.

Patients who have received prior radiotherapy to the mediastinal/pericardial area should not receive doxorubicin greater than a total cumulative dose of 400 mg/m².

Dosage may also need to be reduced in young children and the elderly. It is recommended that the total cumulative dose of doxorubicin for adults aged 70 or older be restricted to 450 mg/m² body surface area.

4.2.2 For intravesical use

Doxorubicin may be used by intravesical instillation for the treatment of superficial bladder carcinoma after transurethral resection. However, this method is contraindicated in invasive bladder tumours.

The patient should not drink fluids for 12 hours prior to the treatment.

25 ml of the solution, containing 50 mg of doxorubicin hydrochloride, is mixed under sterile conditions with 20 ml normal saline and instilled via catheter into the bladder.

After removal of the catheter, the patient stays lying on his back for 15 minutes.

At 15-minute intervals, the patient makes a quarter turn over a period of 1 hour. At the end of this period, the patient may void.

This procedure can be repeated at monthly intervals.

4.2.3 Impaired hepatic function

If hepatic function is impaired, the dosage should be reduced according to the following table:

Serum Bilirubin Levels	Bromsulphophthalein Retention	Recommended Dose
1.2 – 3.0 mg/100ml	9 - 15%	50% normal dose
> 3.0 mg/100ml	>15%	25% normal Dose

4.3 Contraindications

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

Doxorubicin Hydrochloride is contra-indicated in patients with pre-existing myelosuppression (e.g. induced by previous antitumour treatment).

Dosage should not be repeated in the presence or development of bone marrow depression or buccal ulceration. The latter may be preceded by premonitory buccal burning sensations and repetition in the presence of this symptom is not advised.

Doxorubicin Hydrochloride is contraindicated in patients with impaired cardiac function and in patients who have been treated previously with complete cumulative doses of anthracyclines (see section 4.4, Special warnings and precautions for use). In patients who have received anthracyclines previously, addition of further anthracycline therapy can be contemplated only after careful assessment of the cardiac status of the patient. The potential benefit of additional anthracycline therapy must carefully be weighed against the possible risks of cardiotoxicity.

Doxorubicin Hydrochloride is further contraindicated in patients with increased haemorrhagic tendency, stomatitis, generalised infections, markedly impaired liver function and cystitis (in the case of intravesical application).

4.4 Special Warnings And Precautions For Use

A cumulative dose of 450 - 500 mg/m² should only be exceeded with extreme caution. Above this level, the risk of irreversible congestive cardiac failure increases greatly, but this condition could even occur with doses of 240 mg/m². These effects may occur during infusion, but also several weeks after termination of therapy.

Cardiac failure may not respond to treatment. Early clinical diagnosis of drug-induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest. Severe cardiac toxicity may occur precipitously without antecedent ECG changes. Base line ECG and periodic follow up ECG during and immediately after active drug therapy is an advisable precaution. Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias are not considered indications for suspension of doxorubicin therapy. A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity. If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.

Precaution is also required during simultaneous or previous radiotherapy of the mediastinal/pericardial area or after treatment with other cardiotoxic substances.

Doxorubicin must not be given intrathecally or intramuscularly or by long-term infusion. Direct intravenous infusion is not advised due to the tissue damage that may occur if the infusion infiltrates the tissues. If a central vein catheter is used then infusion of doxorubicin in sodium chloride 0.9% injection is advised.

Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration.

On intravenous administration of doxorubicin, a stinging or burning sensation signifies extravasation. Even if blood return from aspiration of the infusion needle is good, the injection or infusion should be immediately terminated and restarted in another vein. In the event of inadvertent extravasation, ice packs should be applied to the injection site. Local injection of dexamethasone or hydrocortisone may be used to minimise local tissue necrosis. Hydrocortisone cream 1% may also be applied locally.

Careful haematological monitoring is required due to the myelosuppressive effects. Pre-treatment with digoxin (250 μg daily starting 7 days before doxorubicin) showed a protective effect against cardiotoxicity. In cases of hyperuricaemia, an application of xanthinoxidase-blocking drugs may be indicated.

Like all chemotherapy, therapy with doxorubicin hydrochloride should be carried out only under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

This medicinal product contains 3.5 mg sodium per 1 ml of doxorubicin hydrochloride solution for infusion. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of other antineoplastic agents, e.g.: anthracyclines (daunorubicin, epirubicin, idarubicin), cisplatin, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, fluorouracil, mitomycin C and taxanes can potentiate the risk of doxorubicin-induced congestive heart failure. The disposition of doxorubicin was found to be significantly altered when it was administered immediately after a short intravenous infusion of paclitaxel. The co-administration of paclitaxel causes a decreased clearance of doxorubicin and more neutropenic and stomatitis episodes have been observed.

Increased cardiotoxicity has also been reported after simultaneous intake of cardioactive drugs, e.g., calcium channel blockers and verapamil (with an increase of doxorubicin peak levels, terminal-half life and volume of distribution). The bioavailibility of digoxin decreases during doxorubicin therapy. Careful monitoring of the heart function is required in all such concomitant therapeutic regimens.

Inhibitors of cytochrome P-450 (e.g. cimetidine) may decrease the metabolism of doxorubicin, with a possible increase in toxic effects, especially in cardiotoxicity. Drugs inducing cytochrome P-450 (e.g. rifampicin, barbiturates including phenobarbital) may increase the metabolism of doxorubicin, possibly decreasing the efficacy of doxorubicin.

If doxorubicin therapy is followed by administration of cyclophosphamide, an increased rate of haemorrhagic cystitis has been reported.

The absorption of antiepileptic drugs (e.g. carbamazepine, phenytoin, valproate) is decreased after concomitant use of doxorubicin.

As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the concomitant administration of known hepatotoxic chemotherapeutic agents (e.g. mercaptopurine, methotrexate, streptozocin) could potentially increase the toxicity of doxorubicin as a result of reduced hepatic clearance of the drug. Dosing of doxorubicin must be modified if concomitant therapy with hepatotoxic drugs is mandatory.

Co-administration of heparin and doxorubicin can lead to an increase in the rate of doxorubicin clearance. Furthermore, precipitates may form and lead to a loss of efficacy of both drugs (see section 6.2, Incompatibilities).

Disturbed haemotopoesis has been observed after co-administration of substances influencing the bone-marrow function (e.g. amidopyrine derivatives, antiretroviral drugs, chloramphenicol, phenytoin, sulphonamides). Increased neutropenia and thrombocytopenia have been reported after simultaneous use of progesterone. Marked nephrotoxicity of Amphotericin B can occur during doxorubicin therapy.

Live vaccines must not be used during doxorubicin therapy due to the risk of generalised disease, which may be lethal. The risk is increased in patients who are immunodepressed due to the underlying disease.

4.6 Pregnancy And Lactation

Pregnancy

Doxorubicin has been found in foetal tissue (liver, kidney, lungs) at concentrations several times those in maternal plasma indicating that it does pass the placenta. Doxorubicin proved to be highly teratogenic in rats and mutagenic in the Ames test. Pregnancy is therefore a contraindication for Doxorubicin Hydrochloride.

For safety reasons, men wanting a baby should preserve unexposed sperm prior to treatment with doxorubicin and abstain from engendering a child during and 6 months after therapy. Women with childbearing potential should avoid pregnancy during doxorubicin therapy and 6 months thereafter.

Lactation

The drug has been shown to concentrate in human milk. Because of the potential for serious adverse reactions in nursing infants a decision should be made whether to discontinue breast-feeding or the drug, taking into account the importance of the drug for the woman.

4.7 Effects On Ability To Drive And Use Machines

Drowsiness may occur.

4.8 Undesirable Effects

4.8.1 General

Bone Marrow Depression (myelosuppression): There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring. With the recommended dosage schedule, leukopenia is usually transient, reaching its nadir at 10 – 14 days after treatment, with recovery usually occurring by the 21^st day. White blood cell counts as low as 1000/mm³ are to be expected during treatment with ap-propriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored, since they may also be depressed.

Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function (when appropriate dosage reduction has not been adopted) and simultaneous treatment with other myelosuppressive agents. Haematological toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Persistent severe myelosuppression may result in superinfection or haemorrhage.

Immunosuppression: Doxorubicin is a powerful but temporary immunosuppressant agent. Appropriate measures should be taken to prevent secondary infection.

Enhanced toxicity: It has been reported that doxorubicin may enhance the severity of the toxicity of other anticancer therapies, such as cyclophosphamide induced haemorrhagic cystitis, mucositis induced by radiotherapy, hepatotoxicity of 6

Infertility: Doxorubicin may cause infertility during the time of drug administration. Although ovulation and menstruation appear to return after termination of therapy, there is only scarce information about the restoration of male fertility.

Hepatic impairment: Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment. It is recommended that an evaluation of hepatic function be carried out prior to individual dosing, using conventional clinical laboratory tests such as AST, ALT, alkaline phosphatase, bilirubin and BSP. If required, dosage schedules should be reduced accordingly (see section 4.2, Posology and method of administration).

The occurrence of secondary acute myeloid leukaemia with or without a pre-leukaemic phase has been reported rarely in patients concurrently treated with doxorubicin in association with DNA damaging antineoplastic agents. Such cases could have a short (1 - 3 year) latency period.

4.8.2 Adverse reactions

4.8.2.1 More frequent reactions

Cardiovascular: Cardiotoxicity, i.e., cardiomyopathy, congestive heart failure, supraventricular tachycardia. Routine ECG monitoring is recommended and caution should be exercised in patients with impaired cardiac function. Severe cardiac failure may occur suddenly, without premonitory ECG changes.

Vascular system: Phlebosclerosis.

Dermatological: Extravasation, skin necrosis, cellulitis, vesication, phlebitis, erythematous streaking along the vein proximal to the site of injection. Alopecia occurs frequently, including the interruption of beard growth, but all hair growth normally returns after treatment is stopped.

The risk of thrombophlebitis at the injection site may be minimised by following the procedure for administration recommended above (see section 4.2, Posology and method of administration).

Gastrointestinal: Nausea and vomiting, mucositis (stomatitis and oesophagitis), diarrhoea, anorexia, ulceration and necrosis of the colon. Mucositis is a frequent and painful complication of doxorubicin treatment. It most commonly develops 5 to 10 days after treatment, and typically begins as a burning sensation in the mouth and pharynx. It may involve the vagina, rectum and oesophagus, and progress to ulceration with risk of secondary infection and usually subsides in 10 days. Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase. Mucositis may be severe in patients who have had previous irradiation to the mucosae.

General: Dehydration, facial flushing (if an injection has been given too rapidly). Doxorubicin may impart a red colour to the urine particularly to the first specimen passed after the injection, and patients should be advised that there is no cause for alarm.

4.8.2.2 Less frequent reactions

Dermatological: Urticarial rash, onycholysis, hyperpigmentation of nail beds and dermal increases (primarily in children in a few cases), recall of skin reaction due to prior radiotherapy.

Allergy: Fever, chills, urticaria, anaphylaxis.

Nervous System: Drowsiness.

Ocular: Conjunctivitis, lacrimation.

Renal: Renal damage.

4.9 Overdose

The symptoms of overdosage are likely to be an extension of doxorubicin's pharmacological action. Single doses of 250 mg and 500 mg of doxorubicin have proven to be fatal. Such doses may cause acute myocardial degeneration within 24 hours, and severe myelosuppression, the greatest effects of which are seen between 10 and 15 days after administration. Delayed cardiac failure may occur up to six months after the overdose. Treatment should aim to support the patient during this period. Particular attention should be given to prevention and treatment of possible severe haemorrhage or infections secondary to severe, persistent bone marrow depression. Blood transfusion and reverse barrier nursing may be considered. Hemoperfusion immediately after the overdose proved to be a rescue measure, too.

Delayed cardiac failure may occur up to six month after the overdose. Patients should be observed carefully and, should signs of cardiac failure arise, be treated along conventional lines.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances)

ATC code: L01DB01

Doxorubicin is an anthracycline antibiotic. It exerts its antineoplastic effect via cytotoxic mechanisms of action, especially intercalation into DNA, inhibition of the enzyme topoisomerase II, and formation of reactive oxygen species (ROS). All of these have a deleterious effect on DNA synthesis: Intercalation of the doxorubicin molecule leads to an inhibition of RNA and DNA polymerases by way of disturbances in base recognition and sequence specificity. The inhibition of topoisomerase II produces single and double strand breaks of the DNA helix. Scission of DNA also originates from the chemical reaction with highly reactive oxygen species like the hydroxyl radical OH^.. Mutagenesis and chromosomal aberrations are the consequences.

The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are the main normal tissues damaged.

An important cause of treatment failure with doxorubicin and other anthracyclines is the development of resistance. In an attempt to overcome cellular resistance to doxorubicin, the use of calcium antagonists such as verapamil has been considered since the primary target is the cell membrane. Verapamil inhibits the slow channel of calcium transport and can enhance cellular uptake of doxorubicin. A combination of doxorubicin and verapamil is associated with severe toxic effects in animal experiments.

5.2 Pharmacokinetic Properties

Following intravenous injection, doxorubicin is rapidly cleared from the blood, and distributed into tissues including lungs, liver, heart, spleen, lymph nodes, bone marrow and kidneys. Relatively low but persistent levels are found in tumour tissue.

Doxorubicin undergoes rapid metabolism in the liver. Doxorubicinol is the most common metabolite, although a substantial fraction of patients forms doxorubicin

The volume of distribution V_d is 25 l; the degree of protein binding is 60–70%. There is substantial interpatient variation in biotransformation. Clearance is apparently not dose-related, but it is higher in men than in women.

Impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Dose reduction is generally advised although there is no clear relationship between liver function tests, doxorubicin clearance and clinical toxicity. Since doxorubicin and metabolites are excreted in the urine only to a minor degree, there are no clear indications that the pharmacokinetics or toxicity of doxorubicin are altered in patients with impaired renal function.

5.3 Preclinical Safety Data

Doxorubicin behaves as a typical inhibitor of cellular reproduction. Cytotoxicity to the most actively proliferating tissues is more prevalent and occurs earlier with respect to parenchymal damage.

5.3.1 Single dose toxicity

Intravenous LD₅₀ values in different animal species have been reported as follows:

Mouse 9 – 21 mg/kg, rat 8 – 14 mg/kg, rabbit 6 mg/kg and dog 2.5 mg/kg. A clear dose-dependent acute toxicity was observed.

5.3.2 Repeated dose toxicity

In clinical practice, the chronic toxicity of doxorubicin is rather similar to that of other comparable cytotoxic substances used in chemotherapy of malignant neoplasms. However, due to its cardiotoxic adverse effects doxorubicin notably warrants special precautions (cf. section 4.8.2.1).

Intravenous doses of 0.125 to 0.5 mg/kg/d were given to rabbits and dogs for 3 months. The lowest dose caused neither mortality nor other signs of toxicity (except for a mild inhibition of spermatogenesis). With the higher doses mortality, hemorrhagic enterocolitis, arrest or reduction of body growth, alopecia and melanosis, total depression of hemopoiesis with particular damage to the platelets, blood coagulation changes, hypoproteinemia, hyperazotemia, morphologic renal damage and depression of spermatogenesis was observed.

5.3.3 Tumorigenicity and mutagenicity

Single i.v. doses of doxorubicin induce mammary tumours in rats. It is also highly potent in producing malignant transformations and mutations in mammalian cell systems in vitro. In the Salmonella/microsome mutagenicity test system (Salmonella typhimurium + rat liver microsome S

Doxorubicin proved to be mutagenic in the standard plate incorporation method of the Ames reversion test. Doxorubicin was also strongly mutagenic against the frameshift-sensitive strain TA98, especially when Cu⁺⁺ ions were present. In the dominant lethal heritable translocation and morphological specific locus test doxorubicin did not induce dominant lethal mutations in murine male germ cells but did induce dominant lethal mutations in female oocytes. In the cytokinesis-block micronucleus assay, it demonstrated a significant increase in the rate of micronucleated cells and of chromosomal aberrations.

5.3.4 Toxicity to reproduction

With respect to fertility, embryonal and foetal toxicity clinical data in man are incomplete. A termination of pregnancy may not always be mandatory and can only be judged in individual cases. In any case, cardiologic and blood tests in the foetus or newborn child is strongly recommended. The risk of malformations and malfunctions in children is considered to be high. Doxorubicin has been found in foetal tissue (liver, kidney, lungs) at concentrations several times those in maternal plasma indicating that it passes the placenta. Doxorubicin proved to be highly teratogenic in rats and mutagenic in the Ames test. Pregnancy is therefore a contraindication for Doxorubicin Hydrochloride.

In animal experiments, toxic effects of doxorubicin on reproduction were observed. In the rat, doxorubicin is teratogenic after i.p. doses as low as 1.25 mg/kg/day. Characteristic malformations included oesophageal and intestinal atresia, tracheoesophageal fistula, hypoplasia of the urinary bladder and various cardiovascular anomalies. The frequency of anomalies rose sharply as the dose increased. At 2.25 mg/kg/day, all embryos were abnormal, and doxorubicin at 2.5 mg/kg/day led to resorption of all embryos. Teratogenicity in late organogenesis (reduction anomalies of the distal limbs) was also demonstrated in rat embryo cultures in the concentration range of 0.1 – 20 μMol/l.

In another experiment with female Sprague-Dawley rats, treated i.p. 1 - 10 mg/kg doxorubicin, the examination of the embryos revealed specific teratogenic effects on the caudal region. Histological examination showed signs of cell death at the level of the gut epithelium and bronchial bar mesenchyme. In the latter experiment, the highest dose of doxorubicin was maternolethal. The foetuses showed a dose-related increase of specific malformations of the digestive system (oesophageal and intestinal atresia, stomach hypoplasia,), urinary system (bladder agenesis or hypoplasia, hydronephrosis), and cardiovascular malformations.

The doxorubicin-treated foetal rat is an excellent model for studying the so-called VATER association (Vertebral defects, Anorectal anomaly, TracheoEsophageal fistula with oesophageal atresia, and Radial dysplasia). Exposure of the rat foetus produces a spectrum of anomalies, including oesophageal atresia and other features of VATER association. Vertebral and rib anomalies e.g. were found in 54 % and limb anomalies in 35% of foetuses exposed to teratogenic doses of doxorubicin in utero.

In rats decreased weights of genital organs, an extremely decreased sperm count, a low sperm motility, a low implantation rate, a decreased number of spermatogonia and a decreased number of live foetuses were observed after 4 weeks of treatment with doses of 1 or 2 mg/kg. After 9 weeks of treatment, genital organs showed atrophy.

Doxorubicin was not teratogenic in the rabbit when given at i.v. doses up to 0.6 mg/kg/day, but a high incidence of abortion occurred.

In the chicken, doxorubicin is toxic and teratogenic during the period of early organogenesis of the chick embryos after eggs received a single injection on days 1 and 2 of incubation. Doxorubicin caused embryonic death, stunted growth, and various gross morphological malformations. LD₅₀ values were 2.5 μg/egg on day 1 and 0.9 μg/egg on day 2.

5.3.5 Neurotoxicity

In ganglion cells of the peripheral nervous system and in spinal, paravertebral and trigeminal ganglia, loss of neurones was observed in rats after i.v. injections of 10 mg/kg. The animals developed severe posterior limb ataxia and mild ataxia of the forelimbs.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections

Sodium chloride

Hydrochloric acid (for pH adjustment)

6.2 Incompatibilities

Doxorubicin should not be mixed with heparin as a precipitate may form and it should not be mixed with 5-fluorouracil as degradation may occur. Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.

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

6.3 Shelf Life

Unopened vials: 2 years

Opened vials: The product should be used immediately after opening the vial.

Prepared infusion solutions :

Chemical and physical in-use stability has been demonstrated in sodium chloride 0.9 % and glucose 5 % for up to 48 hours at 2 – 8°C and for up to 24 hours at 25°C when prepared in glass containers protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted product see section 6.3.

6.5 Nature And Contents Of Container

Colourless glass vials (type I glass) with nominal volumes of 5 ml, 10 ml, 25 ml, 75 ml or 100 ml. Chlorobutyl rubber stoppers with ETFE layer.

Original pack containing 1 vial of 5 ml / 10 ml / 25 ml / 75 ml / 100 ml.

Original pack containing 5 vials of 25 ml each.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

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

Observe guidelines for handling cytotoxic drugs.

The following protective recommendations are given due to the toxic nature of this substance:

− Personnel should be trained in good technique for handling.

− Pregnant staff should be excluded from working with this drug.

− Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.

− A designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed and absorbent paper.

− All items used for administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature (700°C) incineration.

− In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush.

− In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.

− Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably soaking overnight and then rinse with water.

− All cleaning materials should be disposed of as indicated previously.

− Always wash hands after removing gloves.

7. Marketing Authorisation Holder

hameln pharma plus gmbh

Langes Feld 13

31789 Hameln / GERMANY

8. Marketing Authorisation Number(S)

PL 25215/0023

9. Date Of First Authorisation/Renewal Of The Authorisation

01/08/2008

10. Date Of Revision Of The Text

Alka-Mints

Generic Name: calcium carbonate (KAL see um KAR boe nate)

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What is Alka-Mints (calcium carbonate)?

Calcium is a mineral that is found naturally in foods. Calcium is necessary for many normal functions of the body, especially bone formation and maintenance. Calcium can also bind to other minerals (such as phosphate) and aid in their removal from the body.

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What is the most important information I should know about Alka-Mints (calcium carbonate)?

Do not take calcium carbonate or antacids that contain calcium without first asking your doctor if you also take other medicines. Calcium can make it harder for your body to absorb certain medicines. Calcium carbonate works best if you take it with food.

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Talk to your doctor before taking calcium carbonate if you are pregnant. Talk to your doctor before taking calcium carbonate if you are breast-feeding a baby.

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Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

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Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, decreased appetite, constipation, confusion, delirium, stupor, and coma.

What should I avoid while taking Alka-Mints (calcium carbonate)?

Follow your healthcare provider's instructions about any restrictions on food, beverages, or activity.

Alka-Mints (calcium carbonate) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include:

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  decreased appetite;

  
  


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  constipation;

  
  


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This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs can affect Alka-Mints (calcium carbonate)?

Calcium carbonate can make it harder for your body to absorb other medications you take by mouth. Tell your doctor if you are taking:

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  doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

  
  

This list is not complete and other drugs may interact with calcium carbonate. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

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• Alka-Mints Side Effects (in more detail)
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• Erosive Esophagitis
• GERD
• Indigestion
• Stomach Ulcer

Where can I get more information?

• Your doctor or pharmacist can provide more information about calcium carbonate.

See also: Alka-Mints side effects (in more detail)

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

Duphalac 200ml

Duphalac

3.35g/5ml lactulose solution

Relieves Constipation

200ml

Duphalac

3.35g/5ml, Lactulose solution

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription. However, you still need to take Duphalac carefully to get the best results from it.

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


• Ask your pharmacist if you need more information or advice.


• You should contact a doctor if your symptoms worsen or do not improve.


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

In this leaflet:

• 1. What Duphalac is and what it is used for


• 2. Before you take Duphalac


• 3. How to take Duphalac


• 4. Possible side effects


• 5. How to store Duphalac


• 6. Further information

What Duphalac is and what it is used for

Duphalac contains a medicine called lactulose. This belongs to a group of medicines called laxatives.

Duphalac is used to treat constipation. It is also sometimes used to treat a liver problem called ‘hepatic encephalopathy’.

This is also known as a ‘hepatic coma’.

Before you take Duphalac

Do not take Duphalac if:

• You are allergic (hypersensitive) to lactulose or any of the other ingredients of Duphalac (listed in Section 6).


• You have a rare problem called ‘galactosaemia’.


• You have a blockage caused by anything else but normal constipation

Do not take Duphalac if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Duphalac.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, might become pregnant or are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine, if you are pregnant or breast-feeding. Duphalac is safe to take in normal doses during pregnancy and when breast-feeding.

Important information about some of the ingredients of Duphalac

Duphalac contains fructose, galactose and lactose (all are types of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars (have an intolerance to some sugars), talk to your doctor before taking this medicine.

How to take Duphalac

If this medicine is from your doctor or pharmacist, do exactly as they have told you. Otherwise follow the instructions below. If you do not understand the instructions, or you are not sure, ask your doctor or pharmacist.

Taking this medicine

• Take Duphalac from a spoon or measuring cup.


• You can mix it with fruit juice or water.


• Duphalac takes 2 to 3 days to start working.


• After this time you may be able to reduce the dose you take according to your needs.

Constipation

Adults: The usual starting dose is 15 ml twice a day.

Children 5 to 10 years: The usual starting dose is 10 ml twice a day.

Children under 5 years: The usual starting dose is 5 ml twice a day

Babies under 1 year: The usual starting dose is 2.5 ml twice a day.

Hepatic encephalophathy

Adults: The usual starting dose is 30 to 50ml three times a day.

If you take more Duphalac than you should

If you take more Duphalac than you should, talk to a doctor. You may have diarrhoea.

If you forget to take Duphalac

• If you forget a dose, take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose.


• Do not take a double dose to make up for a forgotten dose.

Duphalac 200ml Side Effects

Like all medicines, Duphalac can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

• Increased wind and feeling bloated. This may happen during the first few days of treatment. These effects usually disappear after a few days.


• Diarrhoea. This may happen if you take high doses of Duphalac. If this happens, lower your dose.

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

How to store Duphalac

Keep out of the reach and sight of children.

Do not use Duphalac after the expiry date on the bottle.

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

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

Further information

What Duphalac contains

• The active substance is lactulose. Each 5ml of Duphalac contains 3.35g of lactulose.


• The other ingredients are water, lactose, galactose, epilactose, fructose, tagatose, hydrogen peroxide and sodium hydroxide.

What Duphalac looks like and contents of the pack

• Duphalac is a colourless or yellow liquid.


• Duphalac is available in plastic bottles containing 200ml, 300ml, 500ml and 1000ml.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is

Solvay Healthcare Limited

Southampton

SO18 3JD

The manufacturer is

Solvay Biologicals B.V.

8121 AA

OIst

The Netherlands

This leaflet was last approved in April 2009.

If you wish to receive this PIL in Braille, large font or audio format please contact 023 8046 7000.

Remember

This medicine is for you.

Please do not offer it to your family and friends, even if they have the same symptoms as you.

Duphalac

3.35g/5ml lactulose solution

Relieves Constipation

Duphalac contains a medicine called lactulose.

Each 5ml of Duphalac contains 3.35g of lactulose.

200ml

Duphalac contains a medicine called lactulose.

Each 5ml of Duphalac contains 3.35g of lactulose.

Duphalac contains fructose, galactose and lactose (all are types of sugar).

If you have been told by your doctor that you cannot tolerate or digest some sugars (have an intolerance to some sugars), talk to your doctor before taking this medicine.

Duphalac is a colourless or yellow liquid. Duphalac is available in plastic bottles containing:

200ml, 300ml, 500ml, 1000ml.

Read the package leaflet before use.

Keep out of the reach and sight of children.

Do not use Duphalac after the expiry date on the bottle.

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

This medicine is available without prescription. Duphalac is used to treat constipation. It is also sometimes used to treat a liver problem called ‘hepatic encephalopathy’.

This is also known as a ‘hepatic coma’.

RF1594

Solvay Healthcare

P

PL 00512/5001R

The Marketing Authorisation Holder is

Solvay Healthcare Limited

Southampton

SO18 3JD

trade mark

PIP 212-2620

RF1594

DULCOLAX Tablets, 5 mg (GSL)

1. Name Of The Medicinal Product

DULCOLAX 5 mg Gastro-resistant Tablets

2. Qualitative And Quantitative Composition

Each tablet contains Bisacodyl 5mg.

For excipients, see 6.1

3. Pharmaceutical Form

Gastro-resistant tablets for oral administration.

Circular, biconvex, yellow, sugar-coated and enteric-coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Short term relief of constipation.

4.2 Posology And Method Of Administration

Adults and children over 10 years: 1 to 2 coated tablets (5-10 mg) daily before bedtime.

It is recommended to take the coated tablets at night to have a bowel movement the following morning. They should be swallowed whole with an adequate amount of fluid.

The coated tablets should not be taken together with products which reduce the acidity of the upper gastrointestinal tract, such as milk, antacids or proton pump inhibitors, in order not to prematurely dissolve the enteric coating.

No specific information on the use of this product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

4.3 Contraindications

DULCOLAX is contraindicated in patients with ileus, intestinal obstruction, acute abdominal conditions including appendicitis, acute inflammatory bowel diseases, and severe abdominal pain associated with nausea and vomiting which may be indicative of the aforementioned severe conditions.

DULCOLAX is also contraindicated in severe dehydration and in patients with known hypersensitivity to bisacodyl or any other component of the product.

4.4 Special Warnings And Precautions For Use

As with all laxatives, DULCOLAX should not be taken on a continuous daily basis for more than five days without investigating the cause of constipation.

Prolonged excessive use may lead to fluid and electrolyte imbalance and hypokalaemia.

Intestinal loss of fluids can promote dehydration. Symptoms may include thirst and oliguria. In patients suffering from fluid loss where dehydration may be harmful (e.g. renal insufficiency, elderly patients) DULCOLAX should be discontinued and only be restarted under medical supervision.

Patients may experience haematochezia (blood in stool) that is generally mild and self-limiting.

Dizziness and / or syncope have been reported in patients who have taken DULCOLAX. The details available for these cases suggest that the events would be consistent with defaecation syncope (or syncope attributable to straining at stool), or with a vasovagal response to abdominal pain related to the constipation, and not necessarily to the administration of bisacodyl itself.

There have been isolated reports of abdominal pain and bloody diarrhoea occurring after taking bisacodyl. Some cases have been shown to be associated with colonic mucosal ischaemia.

DULCOLAX should not be taken by children under 10 years without medical advice.

DULCOLAX Tablets contain a small amount of lactose (33.2 mg) and sucrose (23.4 mg) in each tablet. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant use of antacids and milk products may reduce the resistance of the coating of the tablets and result in dyspepsia and gastric irritation.

The concomitant use of diuretics or adreno-corticosteroids may increase the risk of electrolyte imbalance if excessive doses of DULCOLAX are taken.

Electrolyte imbalance may lead to increased sensitivity to cardiac glycosides.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled studies in pregnant women. Long experience has shown no evidence of undesirable or damaging effects during pregnancy.

Clinical data show that neither the active moiety of bisacodyl (BHPM or bis-(p-hydroxyphenyl)-pyridyl-2-methane) nor its glucuronides are excreted into the milk of healthy lactating females.

Nevertheless, as with all medicines, DULCOLAX should not be taken in pregnancy, especially the first trimester, and during breast feeding unless the expected benefit is thought to outweigh any possible risk and only on medical advice.

No studies on the effect on human fertility have been conducted.

4.7 Effects On Ability To Drive And Use Machines

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

However, patients should be advised that due to a vasovagal response (e.g. to abdominal spasm) they may experience dizziness and / or syncope. If patients experience abdominal spasm they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable Effects

The most commonly reported adverse reactions during treatment are abdominal pain and diarrhoea.

Adverse events have been ranked under headings of frequency using the following convention: Very common (

Immune system disorders

Rare: anaphylactic reactions, angioedema, hypersensitivity.

Metabolism and nutrition disorders

Rare: dehydration.

Nervous system disorders

Uncommon: dizziness.

Rare: Syncope.

Dizziness and syncope occurring after taking bisacodyl appear to be consistent with a vasovagal response (e.g. to abdominal spasm, defaecation).

Gastrointestinal disorders

Uncommon: haematochezia (blood in stool), vomiting, abdominal discomfort, anorectal discomfort.

Common: abdominal cramps, abdominal pain, diarrhoea and nausea.

Rare: colitis.

4.9 Overdose

Symptoms

If high doses are taken watery stools (diarrhoea), abdominal cramps and a clinically significant loss of fluid, potassium and other electrolytes can occur.

Laxatives when taken in chronic overdose may cause chronic diarrhoea, abdominal pain, hypokalaemia, secondary hyperaldosteronism and renal calculi. Renal tubular damage, metabolic alkalosis and muscle weakness secondary to hypokalaemia have also been described in association with chronic laxative abuse.

Therapy

After ingestion of oral forms of DULCOLAX, absorption can be minimised or prevented by inducing vomiting or gastric lavage. Replacement of fluids and correction of electrolyte imbalance may be required. This is especially important in the elderly and the young. Administration of antispasmodics may be of value.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Bisacodyl is a locally acting laxative from the diphenylmethane derivatives group having a dual action. As a contact laxative, for which also antiresorptive hydragogue effects have been described, bisacodyl stimulates after hydrolysis in the large intestine, the mucosa of both the large intestine and of the rectum. Stimulation of the mucosa of the large intestine results in colonic peristalsis with promotion of accumulation of water, and consequently electrolytes, in the colonic lumen. This results in a stimulation of defecation, reduction of transit time and softening of the stool. Stimulation of the rectum causes increased motility and a feeling of rectal fullness. The rectal effect may help to restore the “call to stool” although its clinical relevance remains to be established.

5.2 Pharmacokinetic Properties

Following either oral or rectal administration, bisacodyl is rapidly hydrolyzed to the active principle bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), mainly by esterases of the enteric mucosa.

Administration as an enteric coated tablet was found to result in maximum BHPM plasma concentrations between 4 – 10 hours post administration whereas the laxative effect occurred between 6 – 12 hours post administration. In contrast, following the administration as a suppository, the laxative effect occurred on average approximately 20 minutes post administration; in some cases it occurred 45 minutes after administration. The maximum BHPM-plasma concentrations were achieved 0.5 – 3 hours following the administration as a suppository. Hence, the laxative effect of bisacodyl does not correlate with the plasma level of BHPM. Instead, BHPM acts locally in the lower part of the intestine and there is no relationship between the laxative effect and plasma levels of the active moiety. For this reason, bisacodyl coated tablets are formulated to be resistant to gastric and small intestinal juice. This results in a main release of the drug in the colon, which is the desired site of action.

After oral and rectal administration, only small amounts of the drug are absorbed and are almost completely conjugated in the intestinal wall and the liver to form the inactive BHPM glucuronide. The plasma elimination half-life of BHPM glucuronide was estimated to be approximately 16.5 hours. Following the administration of bisacodyl coated tablets, an average of 51.8% of the dose was recovered in the faeces as free BHPM and an average of 10.5% of the dose was recovered in the urine as BHPM glucuronide. Following the administration as a suppository, an average of 3.1% of the dose was recovered as BHPM glucuronide in the urine. Stool contained large amounts of BHPM (90% of the total excretion) in addition to small amounts of unchanged bisacodyl.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Lactose

Maize starch

Soluble maize starch

Glycerol

Magnesium stearate

Tablet coating:

Magnesium stearate

Sucrose

Talc

Acacia

Titanium dioxide (E171)

Methacrylic acid-methylmethacrylate copolymer (1:1)

Methacrylic acid-methylmethacrylate copolymer (1:2)

Castor oil

Macrogol 6000

Yellow iron oxide (E172)

White beeswax

Carnauba wax

Shellac.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container in the outer carton.

6.5 Nature And Contents Of Container

Blister packs consisting of opaque white PVC/PVDC blister foil and aluminium foil (covering foil).

Blister packs consisting of colourless PVC blister foil and aluminium foil (covering foil).

Packs of 6, 8, 10, 20, 30, and 40.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Boehringer Ingelheim Limited,

Ellesfield Avenue,

Bracknell,

Berkshire,

RG12 8YS,

United Kingdom.

Trading as Boehringer Ingelheim Consumer Healthcare

8. Marketing Authorisation Number(S)

PL 00015/0240

9. Date Of First Authorisation/Renewal Of The Authorisation

1 April 1999

10. Date Of Revision Of The Text

May 2011

11. LEGAL CATEGORY

GSL

Disprin Extra

1. Name Of The Medicinal Product

Disprin Extra

2. Qualitative And Quantitative Composition

Active Ingredient	mg/Tablet	Specification
Aspirin	300	Ph Eur
Paracetamol	200	Ph Eur

3. Pharmaceutical Form

Dispersible tablet

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mild to moderate pain, including headache, migraine, neuralgia, toothache, sore throat and aches and pains. Symptomatic relief of rheumatic aches and pains. Symptomatic relief of influenza, feverishness and feverish colds.

4.2 Posology And Method Of Administration

Oral administration.

Adults and children 16 years and over: One or two tablets every 4 hours. Maximum six tablets in 24 hours.

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki's disease).

The normal adult dosage is appropriate for the elderly.

4.3 Contraindications

Hypersensitivity to the active ingredients or any of the other constituents. Should not be given to patients suffering from active peptic ulceration or haemophilia. Children under 16 years.

4.4 Special Warnings And Precautions For Use

If you are receiving regular medical treatment, are asthmatic, allergic to aspirin or have or have had a stomach ulcer, seek your doctor's advice before taking this product.

There is a possible association between aspirin and Reye's Syndrome when given to children. Reye's Syndrome is a very rare disease which affects the brain and liver and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Do not exceed the recommended dose.

Patients should be advised not to take other paracetamol-containing products concurrently.

Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

Labelling includes: Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well.

If symptoms persist, consult your doctor.

Keep out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aspirin may enhance the effects of anticoagulants and inhibit the effects of uricosurics. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast feeding

Aspirin may prolong labour and contribute to maternal and neonatal bleeding, and is best avoided during the last three months of pregnancy and during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

May precipitate bronchospasm and induce attacks of asthma or hypersensitivity in susceptible subjects. May also induce gastrointestinal haemorrhage, occasionally major.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors

If the patient:

(a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes

Or

(b) Regularly consumes ethanol in excess of recommended amounts.

Or

(c) Is likely to be glutathione deplete, e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines (see BNF overdose section).

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Aspirin

Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within 1 hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must betaken into account.

Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urinary pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylic excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Aspirin:

Aspirin inhibits the cyclo-oxygenase enzyme involved in conversion of phospholipids to prostaglandins and its effects on the body are believed to result primarily from prevention of prostaglandin production. These effects include peripheral analgesia, fever reduction, reduction in inflammation and inhibition of platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

Paracetamol:

Paracetamol has both analgesic and antipyretic activity which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system.

5.2 Pharmacokinetic Properties

Aspirin:

Aspirin is rapidly absorbed from the stomach and upper gastrointestinal tract with peak levels after around 20-30 minutes following dissolution. It is subject to first-pass metabolism with an overall bioavailability of around 70%. Metabolism is by conversion to salicylic acid and then by further conversion to other metabolites. These are excreted by the kidneys in both free and conjugated form. The plasma half-life of aspirin is around 15-20 minutes and that of salicylic acid is 2-3 hours.

Paracetamol:

Paracetamol is absorbed rapidly and completely mainly from the small intestine producing peak plasma levels after 15-20 minutes following oral dosing. The systemic availability is subject to first-pass metabolism and varies with dose between 70% and 90%. The drug is rapidly and widely distributed throughout the body and is eliminated from plasma with a half-life of approximately 2 hours. The major metabolites are glucuronide and sulphate conjugates (>80%) which are excreted in urine.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Calcium carbonate, maize starch, citric acid, sterilised talc, crospovidone, sodium lauryl sulphate, saccharin and orange flavour 610297E.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Cardboard carton containing tablets in strips of 30 micron aluminium soft temper foil with the addition of a 12 micron polyester laminate on the unprinted side.

Pack sizes: 4, 8, 12, 16, 24, 48 and 96 tablets. (Those printed in bold are currently marketed).

6.6 Special Precautions For Disposal And Other Handling

Oral administration after dispersion in water.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull,

HU8 7DS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00063/0019.

9. Date Of First Authorisation/Renewal Of The Authorisation

04/03/2009

10. Date Of Revision Of The Text

04/03/2009