Epirubicin hydrochloride 2mg / ml solution for injection or infusion (hameln)

1. Name Of The Medicinal Product

Epirubicin hydrochloride 2 mg/ml solution for injection or infusion

2. Qualitative And Quantitative Composition

1 ml contains 2 mg epirubicin hydrochloride

Each 5 ml vial contains 10 mg epirubicin hydrochloride

Each 10 ml vial contains 20 mg epirubicin hydrochloride

Each 25 ml vial contains 50 mg epirubicin hydrochloride

Each 50 ml vial contains 100 mg epirubicin hydrochloride

Each 100 ml vial contains 200 mg epirubicin hydrochloride

For a full list of excipients, see section 6.1.

1 ml contains 3.5 mg sodium

3. Pharmaceutical Form

Solution for injection or infusion

Red, clear solution

4. Clinical Particulars

4.1 Therapeutic Indications

Intravenous use:

• Breast carcinoma

• Gastric carcinoma

Intravesical use:

• Prophylaxis of recurrences after transurethral resection

4.2 Posology And Method Of Administration

Epirubicin is not active when given orally and is not for intrathecal or intramuscular injection. For instructions on dilution of the product before administration, see section 6.6.

The safety and efficacy of epirubicin in children has not been established.

Intravenous use

It is advisable to give the drug via the tubing of a freely running intravenous infusion after checking that the needle is well placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with infusion solution after the administration of the drug. Extravasation of epirubicin from the vein during injection may give rise to severe tissue lesions, even necrosis. In case of extravasation, administration should be stopped immediately. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

Discard any unused solution.

Conventional doses

When epirubicin is used as a single agent, the recommended dose in adults is generally 60-90 mg/ m² body area; the drug should be injected intravenously over 3

Alternatively, 20-30 mg/ m² may be given weekly during palliative care in order to reduce frequency of adverse reactions or in patients who do not tolerate higher doses in a range as mentioned above.

Dose modification (reduction) following signs of toxicity (specifically severe neutropenia /neutropenic fever and thrombocytopenia, which could persist on day 21 after the first dose) could be required or the following dose could be delayed, as the case of liver impairment.

High doses

Breast cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin ranging from 100 mg/ m² (as a single dose on day 1) to 120 mg/m²(in two divided doses on days 1 and 8) every 3 - 4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen, are recommended.

The most commonly used dosage schedule of epirubicin in metastatic breast cancer, when employed as a single agent for adults, is up to 135 mg/m² administered at 21² has been used and has been reported to produce less clinical toxicity than higher doses given every three weeks.

In metastatic breast cancer, epirubicin usually can be used in combination with cyclophosphamide and 5-fluorouracil (FEC), at a dose of up to 120 mg/m² every 3 weeks.

Epirubicin should be given as an intravenous bolus over 3 ² for conventional dose and 105 ² for high dose schedules) are recommended for patients whose bone marrow function has already been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone-marrow infiltration. The total dose per cycle may be divided over 2 - 3 successive days.

When epirubicin is used in combination with other antitumour agents, the doses need to be adequately reduced.

Impaired liver function

Since the major route of elimination of epirubicin is the hepatobiliary system, the doses should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. Moderate liver impairment (bilirubin: 20 - 50 µmol/l) requires a 50 % reduction of dose, while severe impairment (bilirubin > 50 µmol/l) necessitates a dose reduction of 75 %.

Impaired renal function

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 450 µmol/l).

Intravesical use

Epirubicin may be given by intravesical administration for the treatment of superficial bladder carcinoma and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.

While many regimens have been used, the following may be helpful as a guide: for therapy 8 x weekly instillations of 50 mg/25-50 ml (diluted with 0.9 % sodium chloride injection). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg. For prophylaxis, 4 x weekly administrations of 50 mg/25

For the preparation of the solution for intravesical use see section 6.6.

The solution should be retained intravesically for 1-2 hours. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.

4.3 Contraindications

Epirubicin is contraindicated in patients with marked myelosuppression induced by previous treatment with other antitumour agents or by radiotherapy and in patients already treated with maximal cumulative doses of other anthracyclines such as Doxorubicin or Daunorubicin.

The drug is contraindicated in patients with current or previous history of cardiac impairment (including 4th degree muscular heart failure, acute heart attack and previous heart attack which led to 3rd and 4th degree muscular heart failure, acute inflammatory heart diseases, arrhythmia with serious heamodynamic consequences).

The drug is contraindicated in patients with acute systemic infections.

Epirubicin is contraindicated in patients with hypersensitivity to epirubicin, other antracyclines and/or anthracenediones or to any of the excipients.

Epirubicin is contraindicated in lactating women.

Additional contraindications to the intravesical use are:

invasive tumors that had penetrated the vesical wall; urinary infections; inflammation of the bladder; catheterization problems; contracted bladder; big volume of residual urine

4.4 Special Warnings And Precautions For Use

Epirubicin therapy should be administered only under the supervision of a qualified physician experienced in antiblastic and cytotoxic therapy. Treatment with high dose epirubicin in particular requires the availability of facilities for the care of possible clinical complications due to myelosuppression.

Initial treatment calls for a careful baseline monitoring of various laboratory parameters and cardiac function.

During each cycle of treatment with epirubicin, patients must be carefully and frequently monitored. Red and white blood cells, neutrophils and platelet counts should be carefully assessed both before and during each cycle of therapy. Leukopenia and neutropenia are usually transient with conventional and high-dose schedules, reaching a nadir between the 10^thand 14^th day and returning to normal values by the 21^st day; they are more severe with high dose schedules. Very few patients, even receiving high doses, experience thrombocytopenia (< 100,000 platelets/mm³).

Patients must have adequately recovered from severe stomatitis or mucositis before starting treatment with epirubicin.

Epirubicin is mainly eliminated via the liver. Therefore it is necessary to evaluate liver function (AST, ALT, alkaline phosphatase, bilirubin) prior to initiating treatment and during treatment. In patients with increased bilirubin levels or AST epirubicin clearance can be reduced, which may lead to increased toxicity. For these patients a dose reduction is recommended (see section 4.2). For patients with reduced renal function serum creatinine levels should be checked regularly prior to and during treatment. For patients with increased serum creatinine (>450µmol/l) a dose reduction is proposed (see section 4.2).

A cumulative dose of 900 ² should only be exceeded with extreme caution with both conventional and high doses.

Above this level the risk of irreversible congestive cardiac failure increases greatly. There is objective evidence that cardiac toxicity may occur rarely below this range. However, cardiac function must be carefully monitored during treatment to minimise the risk of cardiac failure of the type described for other anthracyclines.

Heart failure can appear even several weeks after discontinuing treatment and may prove unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial area.

In establishing the maximal cumulative doses of epirubicin, any concomitant therapy with potential cardiotoxic drugs should be taken into account.

It is recommended that an ECG before and after each treatment cycle should be carried out. Alterations in the ECG tracing, such as flattening or inversion of the T

Cardiomyopathy induced by anthracyclines, is associated with a persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving epirubicin treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques such as ECG, echocardiography and, if necessary, measurement of ejection fraction by radionuclide angiography.

Like other cytotoxic agents, epirubicin may induce hyperuricaemia as a result of rapid lysis of neoplastic ells. Blood uric acid levels should therefore be carefully checked so that this phenomenon may be controlled pharmacologically.

Epirubicin may impart a red colour to the urine for 1

This medicinal product contains 3.5 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other anticancer drugs but patients should be monitored for additive toxicity. Concomitant use of other medicinal products that may be cardiotoxic or affect cardiac function should be monitored throughout treatment.

Drug interactions with epirubicin have been observed with cimetidine, verapamil/dexverapamil, dexrazoxane, docetaxel, interferon α₂b, paclitaxel and quinine.Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m² every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter p<0.05). The AUC of the 7-deoxy-doxorubicinol aglycone and liver blood flow were not reduced, so results are not explained by reduced cytochrome P-450 activity.

Verapamil/Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.

Prior administration of higher doses (900 mg/m² and 1200 mg/m²) of dexrazoxane may increase the systemic clearance of epirubicin and result in a decrease in AUC.

One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately after epirubicin.

The co-administration of interferon α₂b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.

Paclitaxel may affect the pharmacokinetics of epirubicin and its metabolite, epirubicinol. In one study, haematological toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin.

One study has shown that paclitaxel clearance is reduced by epirubicin.

Quinine may accelerate the initial distribution of epirubicin from blood into the tissues and may have an influence on the red blood cell partitioning of epirubicin.

The possibility of a marked disturbance of the haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulfonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).

Cardiotoxicity of epirubicin is enhanced by certain radiotherapeutic treatments and by previous or concomitant use of other anthracycline derivates like mitomycin-c, dacarbazine, dactinomycin and possibly cyclophosphamide. Epirubicin can potentate the effect of radiation. Medicinal products that induce the cytochrome P450 system (e.g., rifampicin and barbiturates) can enhance epirubicin metabolism, with consequently reduced efficacy.

4.6 Pregnancy And Lactation

Epirubicin is a potential teratogen and if administered to pregnant women may cause miscarriage, embryotoxicity and foetal death. During pregnancy, particularly the first trimester, cytostatic drugs should only be used on strict indication and when the potential benefits to the mother have been weighed against possible risks to the foetus. Both men and women receiving epirubicin should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during epirubicin therapy, and use effective contraception during treatment with epirubicin.

It is unknown whether epirubicin is excreted in human breast milk. A risk to the breast-feeding infant cannot be excluded. Breast-feeding must be discontinued during treatment with epirubicin.

Fertility

Epirubicin can have genotoxic effects. Therefore, male patients treated with epirubicin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin.

Women should not become pregnant during treatment with epirubicin. Men and women should use an effective method of contraception during treatment and for six months thereafter.

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 with Epirubicin.

Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

4.8 Undesirable Effects

Adverse event frequencies have been categorised as follows:

Very common (

Common (

Uncommon (

Rare (

Infections and infestations:

Common: Fever, infections, pneumonia, sepsis and septic shock may occur as a result of myelosuppression.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Rare: Secondary acute myeloid leukaemia with or without a pre-leukaemic phase, in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents. These leukaemias have a short (1-3 year) latency.

Blood and lymphatic system disorders:

Common: Myelosuppression (leucopenia, granulocytopenia, neutropenia, febrile neutropenia, thrombo-cytopenia, anaemia). Haemorrhage and tissue hypoxia (as a result of myelosuppression) may occur.

High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse effects which are no different from those seen at conventional doses with the exception of reversible severe neutropenia (<500 neutrophils/mm³ for < 7 days) which occurred in the majority of patients. Only a few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.

Immune system disorders:

Common: Allergic reactions following intravesical administration.

Uncommon: Sensitivity to light or hypersensitivity in the case of radiotherapy ("recall phenomenon").

Rare: Anaphylaxis (anaphylactic/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills).

Cardiac disorders:

Rare: Cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (dyspnoea, oedema, enlargement of the liver, ascites, pulmonary oedema, pleural effusions, gallop rhythm), ventricular tachycardia, bradycardia, AV block, bundle-branch block (see Section 4.4).

Vascular disorders:

Uncommon: Thrombophlebitis

Coincidental cases of thromboembolic events (including pulmonary embolism [in isolated cases with fatal outcome]) have occurred.

Gastrointestinal disorders:

Common: Nausea, vomiting, diarrhoea, which can result in dehydration, loss of appetite and abdominal pain. Oesophagitis and hyperpigmentation of the oral mucosa may also occur.

Skin and subcutaneous tissue disorders:

Very common: Alopecia, normally reversible, appears in 60-90 % of treated cases; it is accompanied by lack of beard growth in males.

Common: Hot flushes

Uncommon: Hyperpigmentation of skin and nails. Skin reddening.

Rare: Urticaria.

General disorders and administration site conditions:

Common: Mucositis - may appear 5-10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, ulceration and bleeding, mainly along the side of the tongue and the sublingual mucosa.

Common: Redness along the infusion vein, local phlebitis, phlebosclerosis, local pain and tissue necrosis (following accidental paravenous injection) may occur.

Uncommon: Headache

Rare: Fever, chills, dizziness, amenorrhea, azoospermia, hyperuricaemia (as a result of rapid lysis of neoplastic cells). Hyperpyrexia, malaise, weakness and increased transaminase levels have also been reported.

Injury, poisoning and procedural complications:

Common: Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration.

4.9 Overdose

Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: cytotoxic antibiotics and related substances, anthracyclines. ATC code: L01D B03

The mechanism of action of epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

5.2 Pharmacokinetic Properties

In patients with normal hepatic and renal function, plasma levels after i.v. injection of 60 ² of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours.

These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH-epirubicin) and glucuronides of epirubicin and epirubicinol.

The 4′-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are constantly lower and virtually parallel those of the unchanged drug.

Epirubicin is eliminated mainly through the liver. High plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution.

Urinary excretion accounts for approximately 9

The drug does not cross the blood-brain-barrier. When epirubicin is administered intravesically the systemic absorption is minimal.

5.3 Preclinical Safety Data

Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the rat, rabbit and dog.

Epirubicin, like other anthracyclines, was mutagenic, genotoxic, embryotoxic and carcinogenic in rats.

No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium chloride

6.2 Incompatibilities

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.

Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Unopened container: 2 years

After dilution:

Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion may be further diluted, under aseptic conditions, in Glucose 5 % or Sodium chloride 0.9 %, and administered as an intravenous infusion. The infusion solution is chemically stable when stored in PE infusion bags, prepared under full aseptic conditions:

Sodium chloride 0.9 %: for 2 days at 25°C ± 2°C or for 4 days at 2-8°C protected from light.

Glucose 5 %: for 1 day at 25°C ± 2°C or for 2 days at 2-8°C protected from light.

From the 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 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)

Do not freeze.

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

For 'in use' storage conditions, see section 6.3.

6.5 Nature And Contents Of Container

6 ml, 10 ml, 25 ml, 50 ml, 100 ml colourless glass vial (type I) with a rubber (chlorobutyl) stopper.

Package quantities:

Packs of	1, 5 vials containing	5 ml
	1, 5 vials containing	10 ml
	1, 5 vials containing	25 ml
	1, 5 vials containing	50 ml
	1, 5 vials containing	100 ml

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The product should be brought to room temperature prior to use.

Epirubicin 2 mg/ml may be further diluted in Glucose 5% or Sodium Chloride 0.9%.

The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements

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

Personnel should be trained in good technique for reconstitution and handling.

Pregnant staff should be excluded from working with this drug.

Personnel handling Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should wear protective clothing: goggles, gowns and disposable gloves and masks.

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

All items used for reconstitution, administration or cleaning including gloves should be placed in high-risk, waste disposal bags for high temperature incineration. Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably by soaking, and then water.

All cleaning materials should be disposed of as indicated previously.

In case of skin contact thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. In case of contact with the eye(s), hold back the eyelid of the affected eye(s), and flush with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.

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 25215/0017

9. Date Of First Authorisation/Renewal Of The Authorisation

01/08/2008

10. Date Of Revision Of The Text

01/08/2008

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Tygacil

Generic Name: tigecycline (Intravenous route)

tye-ge-SYE-kleen

Commonly used brand name(s)

In the U.S.

• Tygacil

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antibiotic

Chemical Class: Glycylcycline

Uses For Tygacil

Tigecycline is an antibiotic. It is used to treat bacterial infections in many different parts of the body (e.g., infections on the skin, stomach, or lungs). It works by killing bacteria or preventing their growth. However, this medicine will not work for colds, flu, or other virus infections.

This medicine is available only with your doctor's prescription.

Before Using Tygacil

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of tigecycline in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tigecycline in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Diarrhea from an antibiotic or


• Liver disease or


• Pancreatitis (inflammation of the pancreas)—Use with caution. May make these conditions worse.

• Liver disease, severe—Use with caution. The effects may be increased because of slower removal from the body.

Proper Use of Tygacil

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins. This medicine is given slowly, so the needle will remain in place for about 30 to 60 minutes.

Precautions While Using Tygacil

If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Birth control pills may not work while you are using tigecycline. To keep from getting pregnant, use another form of birth control along with your birth control pills. Other forms include condoms, a diaphragm, or a contraceptive foam or jelly.

This medicine may cause serious allergic reactions, including anaphylaxis, which can be life-threatening and require immediate medical attention. Call your doctor right away if you have itching; hives; hoarseness; shortness of breath; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth after you receive this medicine.

Tigecycline may cause diarrhea, and in some cases it can be severe. Do not take any medicine to treat diarrhea without first checking with your doctor. Diarrhea medicines may make the diarrhea worse or make it last longer. If you have any questions about this or if mild diarrhea continues or gets worse, check with your doctor.

Tigecycline may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. Use a sunscreen when you are outdoors. Wear protective clothing (including a hat) and sunglasses. Avoid sunlamps and tanning beds or booths.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Tygacil Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Cough or hoarseness


• dizziness


• fever or chills


• headache


• lower back or side pain


• pain, warmth, or burning in the fingers, toes, and legs


• painful or difficult urination


• problems with vision or hearing

Less common

• Abdominal or stomach pain


• accumulation of pus


• bloating or swelling of the face, arms, hands, lower legs, or feet


• bluish color


• blurred vision


• changes in skin color


• confusion


• convulsions


• decreased urine


• diarrhea


• difficult or labored breathing


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• dry mouth


• eye pain


• fat in the stool


• flushed, dry skin


• fruit-like breath odor


• general feeling of illness


• increased hunger


• increased thirst


• increased urination


• irregular heartbeat


• loss of appetite


• mood changes


• muscle pain or cramps


• nausea or vomiting


• nervousness


• numbness or tingling in the hands, feet, or lips


• pain


• pale skin


• pounding in the ears


• rapid weight gain


• shortness of breath


• slow or fast heartbeat


• sore throat


• sweating


• swollen, red, tender area of infection


• tenderness


• tightness in the chest


• troubled breathing with exertion


• unexplained weight loss


• unusual bleeding or bruising


• unusual tiredness or weakness


• unusual weight gain or loss


• wheezing

Rare

• Abdominal or stomach cramps


• anxiety


• black, tarry stools


• bleeding gums


• blood in the urine or stools


• chest pain or discomfort


• clay-colored stools


• cold sweats


• coma


• cool, pale skin


• dark urine


• depression


• difficulty in breathing


• itching


• muscle cramps in the hands, arms, feet, legs, or face


• nightmares


• pinpoint red spots on the skin


• rash


• shakiness


• slurred speech


• sores, ulcers, or white spots on the lips or in the mouth


• swelling of the face, ankles, or hands


• swollen glands


• tremor


• unpleasant breath odor


• vomiting of blood


• yellow eyes or skin

Incidence not known

• Bloating


• constipation


• difficulty in swallowing


• hives


• indigestion


• pains in the stomach, side, or abdomen, possibly radiating to the back


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Red streaks on the skin


• swelling, tenderness, or pain at the injection site

Less common

• Acid or sour stomach


• belching


• heartburn


• lack or loss of strength


• sleeplessness


• stomach discomfort, upset, or pain


• trouble sleeping


• unable to sleep

Rare

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site


• change in taste or bad unusual or unpleasant (after) taste


• increased clear or white vaginal discharge


• itching of the vagina or genital area


• pain during sexual intercourse


• sleepiness or unusual drowsiness


• thick, white vaginal discharge with no odor or with a mild odor


• vaginal yeast infection

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Tygacil side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

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• Tygacil Drug Interactions
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• 0 Reviews for Tygacil - Add your own review/rating

• Tygacil Prescribing Information (FDA)


• Tygacil Consumer Overview


• Tygacil Monograph (AHFS DI)


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Humalog Mix 75/25 Pens

Pronunciation: IN-su-lin LIS-pro
Generic Name: Insulin Lispro Protamine/Insulin Lispro
Brand Name: Examples include Humalog Mix 75/25 and Humalog Mix 50/50

Humalog Mix 75/25 Pens are used for:

Treating diabetes mellitus.

Humalog Mix 75/25 Pens are a combination of an intermediate-acting and a fast-acting form of the hormone insulin. It works by helping your body to use sugar properly. This lowers the amount of glucose in the blood, which helps to treat diabetes.

Do NOT use Humalog Mix 75/25 Pens if:

• you are allergic to any ingredient in Humalog Mix 75/25 Pens


• you are having an episode of low blood sugar

Contact your doctor or health care provider right away if any of these apply to you.

Before using Humalog Mix 75/25 Pens:

Some medical conditions may interact with Humalog Mix 75/25 Pens. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you drink alcoholic beverages or smoke


• if you have kidney or liver problems; nerve problems; adrenal, pituitary or thyroid problems; or diabetic ketoacidosis


• if you use 3 or more insulin injections per day


• if you are fasting, have high blood sodium levels, or are on a low salt diet

Some MEDICINES MAY INTERACT with Humalog Mix 75/25 Pens. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), clonidine, guanethidine, lithium, or reserpine because they may increase the risk of high or low blood sugar or may hide the signs and symptoms of low blood sugar, if it occurs


• Angiotensin-converting (ACE) inhibitors (eg, enalapril), disopyramide, fenfluramine, fibrates (eg, clofibrate, gemfibrozil), fluoxetine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), oral medicine for diabetes (eg, glipizide, metformin, nateglinide), pentamidine, propoxyphene, salicylates (eg, aspirin), somatostatin analogs (eg, octreotide), or sulfonamide antibiotics (eg, sulfamethoxazole) because the risk of low blood sugar may be increased


• Corticosteroids (eg, prednisone), danazol, diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, niacin, phenothiazines (eg, chlorpromazine), progesterones (eg, medroxyprogesterone), somatropin, sympathomimetics (eg, albuterol, epinephrine, terbutaline), or thyroid hormones (eg, levothyroxine) because they may decrease Humalog Mix 75/25 Pens's effectiveness, resulting in high blood sugar

This may not be a complete list of all interactions that may occur. Ask your health care provider if Humalog Mix 75/25 Pens may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Humalog Mix 75/25 Pens:

Use Humalog Mix 75/25 Pens as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Humalog Mix 75/25 Pens. Talk to your pharmacist if you have questions about this information.


• Use Humalog Mix 75/25 Pens within 15 minutes before a meal, unless directed otherwise by your doctor.


• If you will be using Humalog Mix 75/25 Pens at home, a health care provider will teach you how to use it. Be sure you understand how to use Humalog Mix 75/25 Pens. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Carefully rotate the vial or container as directed before each injection. This will ensure that the contents are evenly mixed. This combination insulin should look uniformly cloudy or milky.


• Do not use Humalog Mix 75/25 Pens if it contains particles or clumps, is discolored, or if the vial or container is cracked or damaged.


• Do NOT dilute Humalog Mix 75/25 Pens or mix it with other insulin. Do NOT use it in an insulin pump.


• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.


• Injection sites within an injection area (abdomen, thigh, upper arm) must be rotated from one injection to the next.


• Be sure you have purchased the correct insulin. Insulin comes in a variety of containers, including vials, cartridges, and pens. Make sure that you understand how to properly measure and prepare your dose. If you have any questions about measuring and preparing your dose, contact your doctor or pharmacist for information.


• Humalog Mix 75/25 Pens begins lowering blood sugar within minutes after an injection. The effect may last for up to 24 hours.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• It is very important to follow your insulin regimen exactly. Do NOT miss any doses. Ask your doctor for specific instructions to follow in case you should ever miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Humalog Mix 75/25 Pens.

Important safety information:

• Humalog Mix 75/25 Pens may cause dizziness, drowsiness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Humalog Mix 75/25 Pens with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol without discussing it with your doctor. Drinking alcohol may increase the risk of developing high or low blood sugar.


• Do not use more than the recommended dose, use Humalog Mix 75/25 Pens more often than prescribed, or change the type or dose of insulin you are using without checking with your doctor.


• Any change of insulin should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (regular, NPH, lente), species (beef, pork, beef-pork, human), and/or method of manufacture may require a change in dose.


• Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan to use in case of illness. When you are sick, test your blood/urine frequently and call your doctor as instructed.


• Tell your doctor or dentist that you take Humalog Mix 75/25 Pens before you receive any medical or dental care, emergency care, or surgery.


• If you will be traveling across time zones, consult your doctor concerning adjustments in your insulin schedule.


• Carry an ID card at all times that says you have diabetes.


• An insulin reaction resulting from low blood sugar levels (hypoglycemia) may occur if you take too much insulin, skip a meal, or exercise too much. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Developing a fever or infection, eating significantly more than prescribed, or missing your dose of insulin may cause high blood sugar (hyperglycemia). High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If not treated, loss of consciousness, coma, or death may occur. If these symptoms occur, tell your doctor right away.


• Check with your doctor if you notice a depression in the skin or skin thickening at the injection site. You may need to change your injection technique.


• Proper diet, regular exercise, and regular testing of blood sugar are important for best results when using Humalog Mix 75/25 Pens.


• Lab tests, including fasting blood glucose levels and hemoglobin A_1c levels, may be performed while you use Humalog Mix 75/25 Pens. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Humalog Mix 75/25 Pens with caution in the ELDERLY; if low blood sugar occurs, it may be more difficult to recognize in these patients.


• Humalog Mix 75/25 Pens should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Humalog Mix 75/25 Pens while you are pregnant. It is not known if Humalog Mix 75/25 Pens are found in breast milk. If you are or will be breast-feeding while you use Humalog Mix 75/25 Pens, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Humalog Mix 75/25 Pens:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Redness, swelling, itching, or mild pain at the injection site.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; wheezing; muscle pain); changes in vision; chills; confusion; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; mood changes; seizures; slurred speech; swelling; tremor; trouble breathing; trouble concentrating; unusual hunger; unusual sweating; weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Humalog Mix 75/25 side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center or emergency room immediately. Symptoms may include chills; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; nervousness; seizures; shakiness; sweating; tremor; vision changes; weakness.

Proper storage of Humalog Mix 75/25 Pens:

VIALS: Store new (unopened) vials in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze Humalog Mix 75/25 Pens. Store used (open) vials either in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). If refrigeration is not possible, store at room temperature, below 86 degrees F (30 degrees C). Store away from heat and light. If Humalog Mix 75/25 Pens has been frozen or overheated, throw it away. Throw away unrefrigerated or opened vials after 28 days, even if they still contain medicine.

PENS: Store new (unopened) pens in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze Humalog Mix 75/25 Pens. Store used (open) pens at room temperature, below 86 degrees F (30 degrees C). Do NOT store used (open) pens in the refrigerator. Store away from heat and light. If Humalog Mix 75/25 Pens has been frozen or overheated, throw it away. Throw away unrefrigerated or used pens after 10 days, even if they still contain medicine.

Do not leave Humalog Mix 75/25 Pens in a car on a warm or sunny day. Do not use Humalog Mix 75/25 Pens after the expiration date stamped on the label. Keep Humalog Mix 75/25 Pens, as well as syringes and needles, out of the reach of children and away from pets.

General information:

• If you have any questions about Humalog Mix 75/25 Pens, please talk with your doctor, pharmacist, or other health care provider.


• Humalog Mix 75/25 Pens are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Humalog Mix 75/25 Pens. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Humalog Mix 75/25 resources

• Humalog Mix 75/25 Side Effects (in more detail)
• Humalog Mix 75/25 Use in Pregnancy & Breastfeeding
• Humalog Mix 75/25 Drug Interactions
• Humalog Mix 75/25 Support Group
• 1 Review for Humalog Mix 75/25 - Add your own review/rating

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Lamotrigine 100 mg tablets

1. Name Of The Medicinal Product

Lamotrigine 100 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 100 mg lamotrigine.

Excipients:

Lactose: 76mg

Sunset yellow aluminium lake: 0.2mg

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Tablet.

Peach coloured, mottled, shield shaped uncoated tablets debossed with 'D' and '94'on one side and scoreline on the other side.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy:

Adults and adolescents aged 13 years and above

• Adjunctive or monotherapy treatment of partial seizures and generalized seizures, including tonic-clonic seizures.

• Seizures associated with Lennox-Gastaut syndrome. Lamotrigine is given as an adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaout syndrome.

Children and adolescents aged 2 to 12 years

• Adjunctive treatment of partial seizures and generalized seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.

• Monotherapy of typical absence seizures.

Bipolar disorder:

Adults aged 18 years and above

• Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).

Lamotrigine is not indicated for the acute treatment of manic or depressive episodes.

4.2 Posology And Method Of Administration

Lamotrigine tablets or tablet halves should be swallowed whole, and should not be chewed or crushed.

If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

For doses not realisable/practicable with this medicinal product, other strengths of this medicinal product or other pharmaceutical forms and products are available.

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamotrigine in patients who have discontinued Lamotrigine for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing lamotrigine exceeds five half-lives (see section 5.2), Lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Epilepsy

The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5).

Table 1: Adults and adolescents aged 13 years and above - recommended treatment regimen in epilepsy

Treatment regimen	Weeks 1+2	Weeks 3+4	Usual maintenance dose
Monotherapy:	25 mg/day (once a day)	50 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may increased by maximum of 50-100 mg every one to two weeks until optimal response is achieved.   500 mg/day has been required by some patients to achieve desired response.
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 25-50 mg every one to two weeks until optimal response is achieved
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepin phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200-400 mg/day (two divided doses) To achieve maintenance, doses may be increased by maximum of 100 mg every one to two weeks until optimal response is achieved   700mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25 mg/day (once a day)	50 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50-100 mg every one to two weeks until optimal response is achieved
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)

Treatment regimen	Weeks 1+2	Weeks 3+4	Usual maintenance dose
Monotherapy of typical absence seizures:	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1-10 mg/kg/day, although some patients have required higher doses (up to 15 mg/kg/day) to achieve desired response (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6 mg/kg/day every one to two weeks until optimal response is achieved
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any other concomitant medicinal products	0.15 mg/kg/day* (once a day)	0.3 mg/kg/day (once a day)	1-5 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.3 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200mg/day
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepin phenobarbitone primidone rifampicin lopinavir/ritonavir	0.6 mg/kg/day (two divided doses)	1.2 mg/kg/day (two divided doses)	5-15 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400 mg/day.
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1-10 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6mg/kg every one to two weeks until optimal response is achieved, with a maximum of maintenance dose of 200 mg/day
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.
*NOTE: The recommended dosing schedule for children may not be achievable with the current strengths of the tablets.

To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.

If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lamotrigine monotherapy.

Children below 2 years

There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Thus Lamotrigine is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken, see sections 4.4, 5.1 and 5.2.

Bipolar disorder

The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables below. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided below (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

Table 3: Adults aged 18 years and above – recommended dose escalation to the maintenance total daily stabilisation dose in treatment of bipolar disorder

Treatment Regimen	Weeks 1+ 2	Weeks 3 + 4	Week 5	Target Stabilisation Dose (Week 6)*
Monotherapy with lamotrigine OR adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day (once a day or two divided doses)	200 mg/day – usual target dose for optimal response (once a day or two divided doses). Doses in the range 100 – 400 mg/day used in clinical trials
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day – usual target dose for optimal response (once day or two divided doses) Maximum dose of 200 mg/day can be used depending on clinical response
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200 mg/day (two divided doses)	300 mg/day in week 6, If necessary increasing to usual target dose of 400 mg/day in week 7, to achieve optimal response (two divided doses)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the dose escalations as recommended for lamotrigine with concurrent valproate should be used.

* The target stabilisation dose will alter depending on clinical response.

Table 4: Adults aged 18 years and above – maintenance stabilisation total daily dose following withdrawal of concomitant medicinal products in treatment of bipolar disorder

Once the target daily maintenance stabilisation dose has been achieved, other medicinal products may be withdrawn as shown below.

Treatment Regimen	Current lamotrigine stabilisation dose (prior to withdrawal)	Week 1 (beginning with withdrawal)	Week 2	Week 3 onwards*
Withdrawal of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
When valproate is withdrawn, double the stabilisation dose, not exceeding an increase of more than 100 mg/week	100 mg/day	200 mg/day	Maintain this dose (200 mg/day) (two divided doses)
200 mg/day	300 mg/day	400 mg/day	Maintain this dose (400 mg/day)
Withdrawal of inducers of lamotrigine glucuronidation (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are withdrawn: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	400 mg/day	400 mg/day	300 mg/day	200 mg/day
300 mg/day	300 mg/day	225 mg/day	150 mg/day
200 mg/day	200 mg/day	150 mg/day	100 mg/day
Withdrawal of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn	Maintain target dose achieved in dose escalation (200 mg/day; two divided doses) (dose range 100 – 400 mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.
* Dose may be increased to 400 mg/day as needed.

Table 5: Adults aged 18 years and above - adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder

There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:

Treatment Regimen	Current lamotrigine stabilisation dose (prior to addition)	Week 1 (beginning with addition)	Week 2	Week 3 onwards
Addition of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when valproate is added regardless of any concomitant medicinal products	200 mg/day	100 mg/day	Maintain this dose (100 mg/day)
300 mg/day	150 mg/day	Maintain this dose (150 mg/day)
400 mg/day	200 mg/day	Maintain this dose (200 mg/day)
Addition of inducers of lamotrigine glucuronidation in patients NOT taking valproate (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are added without valproate: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	200 mg/day	200 mg/day	300 mg/day	400 mg/day
150 mg/day	150 mg/day	225 mg/day	300 mg/day
100 mg/day	100 mg/day	150 mg/day	200 mg/day
Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are added	Maintain target dose achieved in dose escalation (200 mg/day; dose range 100 – 400 mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

Discontinuation of Lamotrigine in patients with bipolar disorder

In clinical trials, there was no increase in the incidence, severity or type of adverse reactions following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate Lamotrigine without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamotrigine is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).

General dosing recommendations for Lamotrigine in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30 µg/150 µg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold (see sections 4.4 and 4.5). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100 mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases. Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine by 50- 100 mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.

Starting lamotrigine in patients already taking hormonal contraceptives

Dose escalation should follow the normal dose recommendation described in the tables.

Starting and stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation

Adjustment to the recommended maintenance dose of lamotrigine may not be required.

Elderly (above 65 years):

No dose adjustment from the recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly adult population (see section 5.2).

Renal impairment

Caution should be exercised when administering lamotrigine to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients´ concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.4 and 5.2).

Hepatic impairment

Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see section 5.2).

4.3 Contraindications

Hypersensitivity to lamotrigine, sunset yellow aluminium lake or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalization and discontinuation of lamotrigine have also been reported. These have included potentially life threatening rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis (see section 4.8).

In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as Stevens–Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.

The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalization in epileptic children is from 1 in 300 to 1 in 100.

In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:

• high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2)

• concomitant use of valproate (see section 4.2).

Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see section 4.8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.

Clinical worsening and suicide risk

Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomized placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk of lamotrigine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including lamotrigine. Therefore patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Hormonal contraceptives

Effects of hormonal contraceptives on lamotrigine efficacy

The use of an ethinyloestradiol/levonorgestrel (30 µg/150 µg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events. Patients should be monitored with respect to this.

In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see section 4.2). Variations in lamotrigine levels of this order may be associated with adverse effects. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods).

The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.

Effects of lamotrigine on hormonal contraceptive efficacy:

An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestadiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see section 4.5). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded.

Therefore, patients should be instructed to promptly report changes in their menstrual pattern, e.g. breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase, hence there is a possibility of interference with folate metabolism during long-term therapy (see section 4.6). However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.

Renal failure

In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.

Patients taking other preparations containing lamotrigine

Lamotrigine should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.

Excipients of Lamotrigine tablets

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

Lamotrigine 100 mg tablets contains sunset yellow aluminium lake, which may cause allergic reactions.

Development in children

There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.