Terfenadin AL

Terfenadin AL may be available in the countries listed below.

Ingredient matches for Terfenadin AL

Terfenadine

Terfenadine is reported as an ingredient of Terfenadin AL in the following countries:

• Germany

International Drug Name Search

Otredil

Otredil may be available in the countries listed below.

Ingredient matches for Otredil

Ondansetron

Ondansetron hydrochloride dihydrate (a derivative of Ondansetron) is reported as an ingredient of Otredil in the following countries:

• Greece

International Drug Name Search

Terazosin-1A Pharma

Terazosin-1A Pharma may be available in the countries listed below.

Ingredient matches for Terazosin-1A Pharma

Terazosin

Terazosin hydrochloride (a derivative of Terazosin) is reported as an ingredient of Terazosin-1A Pharma in the following countries:

• Germany

International Drug Name Search

Nu-Seals 300

1. Name Of The Medicinal Product

Nu-Seals 300

Aspirin 300mg Gastro-resistant Tablets

2. Qualitative And Quantitative Composition

Acetylsalicylic Acid 300mg

3. Pharmaceutical Form

White, gastro-resistant tablets, coded “300” in red or “GP” in black

4. Clinical Particulars

4.1 Therapeutic Indications

Aspirin has analgesic, antipyretic and anti-inflammatory actions. It can also be used for the secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery (see below).

Aspirin has an anti-thrombotic action, mediated through inhibition of platelet activation, which has been shown to be useful in secondary prophylaxis following myocardial infarction, and in patients with unstable angina or ischaemic stroke including cerebral transient attacks.

Nu-Seals 300 is indicated wherever high and prolonged dosage of aspirin is required. The special coating resists dissolution in gastric juice, but will dissolve readily in the relatively less acid environment of the duodenum. Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 300 is unsuitable for the short-term relief of pain.

4.2 Posology And Method Of Administration

Nu-Seals 300 is for oral administration to adults only.

Analgesic, antipyretic and anti-inflammatory actions: The usual dose of aspirin is 300-900mg repeated three to four times daily according to clinical needs. In acute rheumatic disorders the dose is in the range of 4-8 g daily, taken in divided doses.

Antithrombotic action: Patients should seek the advice of a doctor before commencing therapy for the first time. The usual dosage, for long-term use following myocardial infarction, transient ischaemic attack, or in patients with unstable angina, is 75-150mg once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 300mg a day may be used on the advice of a doctor.

The elderly: Analgesic, antipyretic and anti-inflammatory actions: As for adults. The elderly are more likely to experience gastric side-effects and tinnitus. Antithrombotic action: The risk-benefit ratio has not been fully established.

Children: Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki's disease). See 'Special Warnings and Special Precautions for Use'.

4.3 Contraindications

Hypersensitivity to aspirin. Hypoprothrombinaemia, haemophilia and active peptic ulceration or a history of peptic ulceration.

4.4 Special Warnings And Precautions For Use

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).

Before commencing long-term aspirin therapy for the management of cerebrovascular or cardiovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.

Aspirin decreases platelet adhesiveness and increases bleeding time. Haematological and haemorrhagic effects can occur, and may be severe. Patients should report any unusual bleeding symptoms to their physician.

Salicylates should be used with caution in patients with a history of peptic ulceration or coagulation abnormalities. They may also induce gastro-intestinal haemorrhage, occasionally major.

They may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Aspirin should be used with caution in patients with impaired renal or hepatic function (avoid if severe), or in patients who are dehydrated.

Patients with hypertension should be carefully monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Salicylates may enhance the effect of oral hypoglycaemic agents, phenytoin and sodium valproate. They inhibit the uricosuric effect of probenecid and may increase the toxicity of sulphonamides.

Aspirin may potentiate the effect of heparin and increases the risk of bleeding with oral anticoagulants, antiplatelet agents and fibrinolytics.

Plasma salicylate concentrations may be reduced by concurrent use of corticosteroids, and salicylate toxicity may occur following withdrawal of the corticosteroids. The risk of gastrointestinal ulceration and bleeding may be increased when aspirin and corticosteroids are co-administered.

Concurrent use of aspirin and other NSAIDs should be avoided. Use of two or more NSAID preparations increases the risk of serious gastrointestinal haemorrhage.

Concurrent administration of carbonic anhydrase inhibitors such as acetazolamide and salicylates may result in severe acidosis and increased central nervous system toxicity.

In large doses, salicylates may also decrease insulin requirements.

Patients using gastro-resistant aspirin should be advised against ingesting antacids simultaneously to avoid premature drug release.

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

Pregnancy: Although clinical and epidemiological evidence suggests the safety of aspirin for use in pregnancy, caution should be exercised when considering use in pregnant patients. Aspirin has the ability to alter platelet function and there may be a risk of haemorrhage in infants whose mothers have consumed aspirin during pregnancy. Prolonged pregnancy and labour, with increased bleeding before and after delivery, decreased birth weight and increased rate of stillbirth have been reported with high blood salicylate levels. With high doses there may be premature closure of the ductus arteriosus and possible persistent pulmonary hypertension in the newborn. Analgesic doses of aspirin should be avoided during the last trimester of pregnancy.

Lactation: As aspirin is excreted in breast milk, Nu-Seals should not be taken by patients who are breast-feeding, as there is a risk of Reye's syndrome in the infant. High maternal doses may impair platelet function in the infant.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Gastrointestinal irritation is common in patients taking aspirin preparations, and nausea, vomiting, dyspepsia, gastritis, gastrointestinal erosions and ulceration have been reported. Anaemia may occur following chronic gastrointestinal blood loss or acute haemorrhage.

Aspirin prolongs bleeding time, and bleeding disorders, such as epistaxis, haematuria, purpura, ecchymoses, haemoptysis, gastrointestinal bleeding, haematoma and cerebral haemorrhage have occasionally been reported. Fatalities have occurred.

Hypersensitivity reactions include skin rashes, urticaria, angioedema, asthma, bronchospasm and rarely, anaphylaxis.

Other side effects: urate kidney stones and tinnitus.

4.9 Overdose

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-cardiogenic 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 one 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 be taken into account. Elimination is increased by urinary alkalisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine 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 salicylate 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 and over 70 have increased risk of salicylate toxicity, and may require dialysis at an earlier stage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Aspirin has analgesic, antipyretic and anti-inflammatory actions.

It also has antithrombotic action, which is mediated through inhibition of platelet activation.

Nu-Seals 300 tablets have a gastro-resistant coat sandwiched between a sealing coat and a top coat. The gastro-resistant coat is intended to resist gastric fluid whilst allowing disintegration in the intestinal fluid.

Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 300 is unsuitable for the short-term relief of pain.

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 (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 likely for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

In a bioequivalence study comparing the pharmacokinetics of the 300mg product with 4 x 75mg presentation in human volunteers, measures such as terminal phase half-life, area-under-the curve and peak plasma concentrations were recorded on days 1 and 4. On day 1 salicylate reached a peak plasma concentration of between 10.34 and 31.57 mcg/ml and between 11.76 and 27.47mcg/ml for the 300mg and 75mg tablets respectively. Time to peak concentration ranged from 4 to 8 hours and from 3 to 6 hours respectively. AUC ranged from 54.0 to 131.2 and from 64.3 to 137.6 h.mcg/ml respectively. The terminal phase half-life ranged from 1.33 to 2.63 hours and from 1.47 to 2.59 hours respectively. On day 4 C_max varied from 15.01 to 48.97 mcg/ml for the 300mg tablet and from 11.26 to 60.21 mcg/ml for 4 x 75mg tablets. T_max ranged from 4 to 8 hours and from 3 to 8 hours, whilst AUC ranged from 89.8 to 297.4 h.mcg/ml and from 61.5 to 293.4 h.mcg/ml respectively.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber in addition to that summarised in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize Starch

Hypromellose

Talc

Methacrylic acid – ethyl acrylate (1:1) copolymer dispersion 30 per cent

Polyethylene Glycol 3350

Propylene Glycol

Benzyl Alcohol

Emulsion silicone

Edible Printing Ink – containing either: E124 Red and Shellac or: E172 Black, Shellac and E322 Lecithin

6.2 Incompatibilities

None

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C. Keep containers tightly closed.

6.5 Nature And Contents Of Container

HDPE bottles with screw caps containing 14, 56, 100 or 500 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0063

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 22 May 1973

Date of last renewal of authorisation: 12 May 2006

10. Date Of Revision Of The Text

10^th August 2010

Danol 100mg Capsules, Danol 200mg Capsules

1. Name Of The Medicinal Product

Danol 100mg Capsules

Danol 200mg Capsules

2. Qualitative And Quantitative Composition

Danazol 100mg

Danazol 200mg

For excipients see 6.1

3. Pharmaceutical Form

Capsule

4. Clinical Particulars

4.1 Therapeutic Indications

Danol capsules are recommended for the treatment of:

Endometriosis: treatment of endometriosis-associated symptoms or/and to reduce the extent of endometriosis foci. Danazol may be used either in conjunction with surgery or, as sole hormonal therapy, in patients not responding to other treatments.

Benign fibrocystic breast disease: symptomatic relief of severe pain and tenderness. Danazol should be used only in patients not responsive to other therapeutic measures or for whom such measures are inadvisable.

4.2 Posology And Method Of Administration

Adults:

Danol capsules should be given as a continuous course, dosage being adjusted according to the severity of the condition and the patient's response. A reduction in dosage once a satisfactory response has been achieved may prove possible. In fertile females, Danol capsules should be started during menstruation, preferably on the first day, to avoid exposing a pregnancy to its possible effects. Where doubt exists, appropriate checks should be made to exclude pregnancy before starting medication. Females of child-bearing age should employ non-hormonal contraception throughout the course of treatment.

In endometriosis the recommended dosage is 200mg to 800mg daily in a course of treatment lasting normally three to six months. Dosage should be increased if normal cyclical bleeding still persists after two months therapy, a higher dosage (not exceeding 800mg per day) may also be needed for severe disease.

In benign fibrocystic breast disease, treatment should commence at a dose of 300mg daily, a course of treatment normally lasting 3 to 6 months.

Elderly: Danol is not recommended.

Children: Danol is not recommended.

The capsules are for oral administration.

4.3 Contraindications

1. Pregnancy

2. Breast feeding

3. Markedly impaired hepatic, renal or cardiac function

4. Porphyria

5. Active thrombosis or thromboembolic disease and a history of such events

6. Androgen dependent tumour

7. Undiagnosed abnormal genital bleeding.

4.4 Special Warnings And Precautions For Use

4.4.1 Special warnings

In the event of virilisation, Danol should be withdrawn. Androgenic reactions generally prove reversible, but continued use of Danol after evidence of androgenic virilisation increases the risk of irreversible androgenic effects.

Danol should be stopped if any clinically significant adverse event arises, and particularly if there is evidence of papilloedema, headache, visual disturbances or other signs or symptoms of raised intracranial pressure, jaundice or other indication of significant hepatic disturbance, thrombosis or thromboembolism.

Whilst a course of therapy may need to be repeated, care should be observed as no safety data are available in relation to repeated courses of treatment over time. The long-term risk of 17-alkylated steroids (including benign hepatic adenomata, peliosis hepatis and hepatic carcinoma), should be considered when danazol, which is chemically related to those compounds, is used.

Data, from two case-control epidemiological studies, were pooled to examine the relationship between endometriosis, endometriosis treatments and ovarian cancer. These preliminary results suggest that the use of danazol might increase the baseline risk of ovarian cancer in - patients treated for endometriosis.

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

4.4.2 Precautions

In view of its pharmacology, known interactions and side effects, particular care should be observed when using Danol in patients with hepatic or renal disease, hypertension or other cardiovascular disease and in any state which may be exacerbated by fluid retention as well as in diabetes mellitus, polycythaemia, epilepsy, lipoprotein disorder, and in those who have shown marked or persistent androgenic reaction to previous gonadal steroid therapy.

Caution is advised in patients with migraine.

Until more is known, caution is advised in the use of Danol in the presence of known or suspected malignant disease (see also contra-indications). Before treatment initiation, the presence of hormone-dependent carcinoma should be excluded at least by careful clinical examination, as well as if breast nodules persist or enlarge during danazol treatment.

In addition to clinical monitoring in all patients, appropriate laboratory monitoring should be considered which may include periodic measurement of hepatic function and haematological state. For long-term treatment (> 6 months) or repeated courses of treatment, biannual hepatic ultrasonography is recommended.

Danazol should be initiated during menstruation. An effective, non-hormonal method of contraception should be employed (see Section 4.2 and 4.6 Pregnancy and Lactation).

The lowest effective dose of Danol should always be sought.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anti-convulsant therapy: Danol may affect the plasma level of carbamazepine and possibly the patient's response to this agent and to phenytoin. With phenobarbital it is likely that similar interaction would occur.

Anti-diabetic therapy: Danol can cause insulin resistance.

Oral anti-coagulant therapy: Danol can potentiate the action of warfarin.

Anti-hypertensive therapy: Possibly through promotion of fluid retention, Danol can oppose the action of anti-hypertensive agents.

Ciclosporin and tacrolimus: Danol can increase the plasma level of ciclosporin and tacrolimus, leading to an increase of the renal toxicity of these drugs.

Concomitant steroids: Although specific instances have not been described, it is likely that interactions will occur between Danol and gonadal steroid therapy.

Migraine therapy: Danol may itself provoke migraine and possibly reduce the effectiveness of medication to prevent that condition.

Ethyl alcohol: Subjective intolerance in the form of nausea and shortness of breath has been reported.

Alpha calcidol: Danol may increase the calcaemic response in primary hypoparathyroidism necessitating a reduction in dosage of this agent.

Interactions with laboratory function tests: Danazol treatment may interfere with laboratory determination of testosterone or plasma proteins (See also section 4.8 Undesirable effects)

Statins: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with statins metabolised by CYP3A 4 such as simvastatin, atorvastatin and lovastatin.

4.6 Pregnancy And Lactation

There is epidemiological and toxicological evidence of hazard in human pregnancy. Danazol is known to be associated with the risk of virilisation to the female foetus if administered during human pregnancy. Danazol should not be used during pregnancy. Women of childbearing age should be advised to use an effective, non-hormonal, method of contraception. If the patient conceives during therapy, danazol should be stopped. Danazol has the theoretical potential for androgenic effects in breast-fed infants and therefore either danazol therapy or breast-feeding should be discontinued.

4.7 Effects On Ability To Drive And Use Machines

No special warning is felt necessary.

4.8 Undesirable Effects

Blood and lymphatic system disorders

Increase in red cell and platelet count. Reversible polycythaemia, leucopoenia, thrombocytopenia, eosinophilia and splenic peliosis.

Endocrine disorders

Androgenic effects:

Acne, weight gain, increased appetite, seborrhoea, hirsutism, hair loss, voice change, which may take the form of hoarseness, sore throat or of instability or deepening of pitch. Hypertrophy of the clitoris, fluid retention.

Other endocrine effects:

Menstrual disturbances in the form of spotting, alteration of the timing of the cycle and amenorrhoea. Flushing, vaginal dryness, changes in libido, vaginal irritation and reduction in breast size.

Modest reduction in spermatogenesis.

Metabolism and nutrition disorders

Increased insulin resistance, increase in plasma glucagon, mild impairment of glucose tolerance.

Increase in LDL cholesterol, decrease in HDL cholesterol, affecting all subfractions, and decrease in apolipoproteins AI and AII.

Induction of aminolevulinic acid (ALA) synthetase, and reduction in thyroid binding globulin, T4, with increased uptake of T3 but without disturbance of thyroid stimulating hormone or free levothyroxine index.

Psychiatric disorders

Emotional lability, anxiety, depressed mood and nervousness.

Nervous system disorders

Dizziness, headache, vertigo, benign intracranial hypertension, migraine.

Aggravation of epilepsy, carpal tunnel syndrome.

Eye disorders

Visual disturbances such as blurring of vision, difficulty in focusing, difficulty in wearing contact lenses and refraction disorders requiring correction.

Respiratory, thoracic and mediastinal disorders

Pleuritic pain, interstitial pneumonitis.

Gastrointestinal disorders

Nausea, epigastric pain.

Cardiac disorders

Hypertension, palpitations and tachycardia.

Thrombotic events including sagittal sinus, cerebrovascular thrombosis as well as arterial thrombosis. Myocardial infarction.

Hepatobiliary disorders

Isolated increases in serum transaminase levels, cholestatic jaundice, benign hepatic adenomata and pancreatitis. Peliosis hepatitis as well as malignant hepatic tumour observed with long term use.

Skin and subcutaneous tissue disorders

Rashes, which may be maculopapular, petechial or purpuric and may be accompanied by fever or may take an urticarial form and may be accompanied by facial oedema. Sun-sensitive rash.

Inflammatory erythematosus nodules, changes in skin pigmentation, exfoliative dermatitis and erythema multiforme.

Musculoskeletal and connective tissue disorders

Backache and muscle cramps which can be severe, with elevation of creatine phosphokinase levels. Muscle tremors, fasciculation, limb pain, joint pain and joint swelling.

Renal and urinary disorders

Haematuria with prolonged use in patients with hereditary angioedema.

General disorders and administration site conditions

Fatigue.

4.9 Overdose

Available evidence suggests that acute overdosage would be unlikely to give rise to immediate serious reaction.

In the case of acute overdose consideration should be given to reducing the absorption of the drug with activated charcoal and the patient should be kept under observation in case of any delayed reactions.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Danazol, 17a-pregna-2,4-dien-20-yno(2,3-d)-isoxazol-17-ol, is a synthetic steroid derived from ethisterone. Its pharmacological properties include:

1. Relatively marked affinity for androgen receptors, less marked affinity for progesterone receptors and least affinity for oestrogen receptors. Danazol is a weak androgen but in addition antiandrogenic, progestogenic, antiprogestogenic, oestrogenic and antioestrogenic actions have been observed.

2. Interference with the synthesis of gonadal steroids, possibly by inhibition of the enzymes of steroidogenesis, including 3β hydroxysteroid dehydrogenase,17β hydroxysteroid dehydrogenase, 17 hydroxylase, 17, 20 lyase, 11β hydroxylase, 21 hydroxylase and cholesterol side chain cleavage enzymes, or alternatively by inhibition of the cyclic AMP accumulation usually induced by gonadotrophic hormones in granulosa and luteal cells.

3. Inhibition of the mid-cycle surge of FSH and LH as well as alterations in the pulsatility of LH. Danazol can also reduce the mean plasma levels of these gonadotrophins after the menopause.

4. A wide range of actions on plasma proteins, including increasing prothrombin, plasminogen, antithrombin III, alpha-2 macroglobulin, C1 esterase inhibitor, and erythropoietin and reducing fibrinogen, thyroid binding and sex hormone binding globulins. Danazol increases the proportion and concentration of testosterone carried unbound in plasma.

5 The suppressive effects of danazol on the hypothalmic-pituitary-gonadal axis are reversible, cyclical activity reappearing normally within 60-90 days after therapy.

5.2 Pharmacokinetic Properties

Danazol is absorbed from the gastrointestinal tract, peak plasma concentrations of 50-80ng/ml being reached approximately 2-3 hours after dosing. Compared to the fasting state, the bioavailability has been shown to increase 3 fold when the drug is taken with a meal with a high fat content. It is thought that food stimulates bile flow which facilitates the dissolution and absorption of danazol, a highly lipophilic compound.

The apparent plasma elimination half life of danazol in a single dose is approximately 3-6 hours. With multiple doses this may increase to approximately 26 hours.

None of the metabolites of danazol, which have been isolated, exhibits pituitary inhibiting activity comparable to that of danazol.

Few data on excretion routes and rates exist. In the monkey 36% of a radioactive dose was recoverable in the urine and 48% in the faeces within 96 hours.

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

Capsule

Maize Starch

Lactose monohydrate

Purified talc

Magnesium stearate

Cap -100mg

Titanium dioxide

Gelatin

Black iron oxide

Cap – 200mg

Gelatin

Titanium dioxide

Red iron oxide

Yellow iron oxide

Ink

Shellac

Shellac glaze

Propylene glycol

Black iron oxide

6.2 Incompatibilities

None.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

PVC blister pack compound of polyvinyl chloride (thickness 250µm) sealed to aluminium foil (thickness 20µm). The blisters are then packed in a cardboard carton.

Pack sizes: 60 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford, Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

Danol 100mg: PL 04425/0194

Danol 200mg: PL 11723/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

28^th October 1993

10. Date Of Revision Of The Text

25^th October 2010

LEGAL CATEGORY

POM

Tolterodine

Pronunciation: tol-TER-oh-deen
Generic Name: Tolterodine
Brand Name: Detrol

Tolterodine is used for:

Treating overactive bladder with symptoms of urinary frequency, urgency, and leakage. It may also be used for other conditions as determined by your doctor.

Tolterodine is an antimuscarinic (anticholinergic) agent. It works by blocking a chemical that causes contractions of the bladder.

Do NOT use Tolterodine if:

• you are allergic to any ingredient in Tolterodine or to fesoterodine


• you have uncontrolled narrow-angle glaucoma, trouble urinating, or have slowed emptying of your stomach


• you are taking a solid oral potassium product (eg, tablet)

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

Before using Tolterodine:

Some medical conditions may interact with Tolterodine. 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 have glaucoma; a blockage of the bladder, stomach, or bowel; stomach or bowel problems (eg, slowed moving of the bowel, constipation); spinal cord injury; dementia; liver or kidney problems; or myasthenia gravis (muscle weakness)


• if you or a family member have a history of irregular heartbeat (eg, prolonged QT, long QT syndrome)

Some MEDICINES MAY INTERACT with Tolterodine. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Antiarrhythmics (eg, amiodarone, quinidine) because the risk of irregular heartbeat may be increased


• Solid oral potassium products (eg, tablets) because the risk of stomach or bowel irritation may be increased by Tolterodine


• Other anticholinergics (eg, scopolamine), azole antifungals (eg, itraconazole, ketoconazole, miconazole), cyclosporine, HIV protease inhibitors (eg, ritonavir), macrolide antibiotics (eg, clarithromycin, erythromycin), nefazodone, or vinblastine because they may increase the risk of Tolterodine's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tolterodine 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 Tolterodine:

Use Tolterodine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Tolterodine. Talk to your pharmacist if you have questions about this information.


• Take Tolterodine by mouth with or without food.


• Tolterodine works best if it is taken at the same time each day.


• If you miss a dose of Tolterodine, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tolterodine.

Important safety information:

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


• Do NOT change your dose of Tolterodine without checking with your doctor.


• Tolterodine should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• Caution is advised when using Tolterodine in CHILDREN; they may be more sensitive to its effects, especially an increased risk of urinary tract infection or behavior or attention problems.


• PREGNANCY and BREAST-FEEDING: If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tolterodine while you are pregnant. It is not known if Tolterodine is found in breast milk. Do not breast-feed while taking Tolterodine.

Possible side effects of Tolterodine:

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:

Blurred vision; constipation; dizziness; drowsiness; dry eyes; dry mouth; headache; indigestion; stomach pain.

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, throat, or tongue; unusual hoarseness); chest pain; confusion; difficult or painful urination; disorientation; fainting; fast or irregular heartbeat; hallucinations; memory problems; severe dizziness; swelling of the hands, ankles, or feet.

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: Tolterodine 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 difficulty breathing; difficulty urinating; dilated pupils; dry mouth; excitation; fast heartbeat; hallucinations; seizures.

Proper storage of Tolterodine:

Store Tolterodine at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tolterodine out of the reach of children and away from pets.

General information:

• If you have any questions about Tolterodine, please talk with your doctor, pharmacist, or other health care provider.


• Tolterodine is 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 Tolterodine. 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 Tolterodine resources

• Tolterodine Side Effects (in more detail)
• Tolterodine Dosage
• Tolterodine Use in Pregnancy & Breastfeeding
• Tolterodine Drug Interactions
• Tolterodine Support Group
• 19 Reviews for Tolterodine - Add your own review/rating

• tolterodine Advanced Consumer (Micromedex) - Includes Dosage Information


• Detrol Prescribing Information (FDA)


• Detrol Monograph (AHFS DI)


• Detrol Consumer Overview


• Detrol LA Prescribing Information (FDA)

Compare Tolterodine with other medications

• Overactive Bladder
• Urinary Incontinence

Pro Ampi

Pro Ampi may be available in the countries listed below.

Ingredient matches for Pro Ampi

Pivampicillin

Pivampicillin is reported as an ingredient of Pro Ampi in the following countries:

• Luxembourg

International Drug Name Search

Sildec-PE DM Drops

Generic Name: chlorpheniramine, dextromethorphan, and phenylephrine (klor feh NEER a meen, dex troe meh THOR fan, and feh nill EH frin)

Brand Names: Alka-Seltzer Plus Cold and Cough, C-Phen DM, C-Phen DM Drops, Cardec DM, Cardec DM Drops, Ceron-DM, Ceron-DM Drops, Cerose DM, Corfen-DM, CP Dec DM, CP Dec-DM Drops, De-Chlor DM, De-Chlor DR, Dec-Chlorphen DM, Dex PC, DM-PE-Chlor, Donatussin DM Drops, Ed A-Hist DM, HistadecDM, Maxiphen ADT, Mintuss DR, Nasohist-DM, Neo DM Drops, Nohist-DMX, Norel DM, P Chlor DM, PD-Cof, PD-Cof Drops, Poly-Tussin DM, Quartuss DM, Reme Tussin DM, Rondec-DM, Rondec-DM Drops, Rondex-DM, Rondex-DM Drops, Sildec-PE DM, Sildec-PE DM Drops, Tri-Vent DPC, Trital DM, Tussplex DM, Zotex-12D

What is Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

Chlorpheniramine, dextromethorphan, and phenylephrine is used to treat sneezing, cough, runny or stuffy nose, itchy or watery eyes, hives, skin rash, itching, and other symptoms of allergies and the common cold.

Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

Chlorpheniramine, dextromethorphan, and phenylephrine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body. Do not use any other over-the-counter cough, cold, allergy, or sleep medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains an antihistamine, decongestant, or cough suppressant. Chlorpheniramine, dextromethorphan, and phenylephrine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication.

What should I discuss with my healthcare provider before taking Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body.

Before taking this medication, tell your doctor if you are allergic to chlorpheniramine, dextromethorphan, or phenylephrine, or if you have:

• kidney disease;


• liver disease;


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  a stomach ulcer or a stomach obstruction,

  
  


• 
  

  emphysema or chronic bronchitis; or

  
  


• 
  

  an enlarged prostate or urination problems.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Chlorpheniramine, dextromethorphan, and phenylephrine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Artificially-sweetened liquid forms of cough-and-cold medications may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.

How should I take Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

Use this medication exactly as directed on the label or as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor.

Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Take this medicine with a full glass of water. If you use the effervescent tablet, drop the tablet in 8 ounces of water and allow it to dissolve completely. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Take this medicine with food or milk if it upsets your stomach.

This medication can cause you to have unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.

Store the medication at room temperature away from moisture and heat.

What happens if I miss a dose?

Since cough or cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include feeling restless or nervous, nausea, vomiting, stomach pain, dizziness, drowsiness, dry mouth, warmth or tingly feeling, or seizure (convulsions).

What should I avoid while taking Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication. Before taking this medication, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by this medication.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Do not use any other over-the-counter cough, cold, allergy, or sleep medication without first asking your doctor or pharmacist. Antihistamines, decongestants, and cough suppressants are contained in many medicines available over the counter. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains an antihistamine, decongestant, or cough suppressant.

Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine) 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. Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  fast, pounding, or uneven heartbeat;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure);

  
  


• 
  

  confusion, hallucinations;

  
  


• 
  

  slow, shallow breathing;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or

  
  


• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  blurred vision;

  
  


• 
  

  dry mouth;

  
  


• 
  

  nausea, stomach pain, constipation;

  
  


• 
  

  mild loss of appetite, stomach upset;

  
  


• 
  

  warmth, tingling, or redness under your skin;

  
  


• 
  

  feeling excited or restless;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  restless or excitability (especially in children);

  
  


• 
  

  skin rash or itching;

  
  


• 
  

  dizziness, drowsiness;

  
  


• 
  

  problems with memory or concentration; or

  
  


• 
  

  ringing in your ears.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Sildec-PE DM Drops (chlorpheniramine, dextromethorphan, and phenylephrine)?

Before taking this medication, tell your doctor if you are using any of the following drugs:

• 
  

  an antidepressant;

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


• 
  

  celecoxib (Celebrex);

  
  


• 
  

  cinacalcet (Sensipar);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  quinidine (Quinaglute, Quinidex);

  
  


• 
  

  ranolazine (Ranexa)

  
  


• 
  

  ritonavir (Norvir);

  
  


• 
  

  sibutramine (Meridia);

  
  


• 
  

  terbinafine (Lamisil);

  
  


• 
  

  medicines to treat high blood pressure;

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);

  
  


• 
  

  bladder or urinary medications such as darifenacin (Enablex), oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol); or

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

  
  

This list is not complete and there may be other drugs that can interact with chlorpheniramine, dextromethorphan, and phenylephrine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Sildec-PE DM Drops resources

• Sildec-PE DM Drops Side Effects (in more detail)
• Sildec-PE DM Drops Use in Pregnancy & Breastfeeding
• Sildec-PE DM Drops Drug Interactions
• Sildec-PE DM Drops Support Group
• 0 Reviews for Sildec-PE DM - Add your own review/rating

• Bronkids Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Cardec DM Elixir MedFacts Consumer Leaflet (Wolters Kluwer)


• Ceron-DM Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• Maxiphen ADT MedFacts Consumer Leaflet (Wolters Kluwer)


• Quartuss DM Prescribing Information (FDA)


• Trital DM Prescribing Information (FDA)

Compare Sildec-PE DM Drops with other medications

• Cough and Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine, dextromethorphan, and phenylephrine.

See also: Sildec-PE DM side effects (in more detail)

Levobens-Teva

Levobens-Teva may be available in the countries listed below.

Ingredient matches for Levobens-Teva

Benserazide

Benserazide hydrochloride (a derivative of Benserazide) is reported as an ingredient of Levobens-Teva in the following countries:

• Germany

Levodopa

Levodopa is reported as an ingredient of Levobens-Teva in the following countries:

• Germany

International Drug Name Search

Pantoprazol Teva

Pantoprazol Teva may be available in the countries listed below.

Ingredient matches for Pantoprazol Teva

Pantoprazole

Pantoprazole sodium (a derivative of Pantoprazole) is reported as an ingredient of Pantoprazol Teva in the following countries:

• Germany


• Sweden

International Drug Name Search

Triprolidine Suspension

Pronunciation: trye-PROE-li-deen
Generic Name: Triprolidine
Brand Name: Zymine XR

Triprolidine Suspension is used for:

Preventing or treating symptoms of hay fever or other allergies, such as runny nose, sneezing, itching of the nose and throat, and itchy, watery eyes. It may also be used for other conditions as determined by your doctor.

Triprolidine Suspension is an antihistamine. It works by blocking the action of histamine, reducing the symptoms of an allergic reaction.

Do NOT use Triprolidine Suspension if:

• you are allergic to any ingredient in Triprolidine Suspension or other similar medicines


• you are taking sodium oxybate (GHB)

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

Before using Triprolidine Suspension:

Some medical conditions may interact with Triprolidine Suspension. 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 have a fast, slow, or irregular heartbeat


• if you have a history of asthma; chronic obstructive pulmonary disease (COPD); chronic bronchitis; lung problems (eg, emphysema); shortness of breath; sleep apnea; heart blood vessel problems; stroke; seizures; a blockage of your stomach, intestine, or bladder; difficulty urinating; diabetes; ulcers; an enlarged prostate or other prostate problems; glaucoma; heart problems; high blood pressure; porphyria; phenylketonuria; or an overactive thyroid

Some MEDICINES MAY INTERACT with Triprolidine Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Sodium oxybate (GHB) because an increase in sleep duration and a decrease in the ability to breathe are likely to occur


• Monoamine oxidase inhibitors (MAOIs) (eg, phenelzine) or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Triprolidine Suspension's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Triprolidine Suspension 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 Triprolidine Suspension:

Use Triprolidine Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Triprolidine Suspension by mouth with or without food.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Triprolidine Suspension and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Triprolidine Suspension.

Important safety information:

• Triprolidine Suspension may cause drowsiness, dizziness, or blurred vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Triprolidine Suspension. Using Triprolidine Suspension alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Avoid drinking alcohol or taking other medications that cause drowsiness (eg, sedatives, tranquilizers) while taking Triprolidine Suspension. Triprolidine Suspension will add to the effects of alcohol and other depressants. Ask your pharmacist if you have questions about which medicines are depressants.


• Triprolidine Suspension may cause dizziness. Alcohol, hot weather, exercise, and fever can increase this effect. To prevent it, sit up or stand slowly, especially in the morning. Also, sit or lie down at the first sign of dizziness.


• Do not become overheated in hot weather or during exercise or other activities since heatstroke may occur.


• If you are scheduled for allergy skin testing, check with your doctor. You may need to stop taking Triprolidine Suspension for several days before the test because it may decrease your response to the skin tests.


• Phenylketonuria patients - Triprolidine Suspension contains phenylalanine. If you must have a diet that is low in phenylalanine, ask your pharmacist if it is in your product.


• If your symptoms do not get better, or if they get worse, or if they occur with a fever, contact your doctor.


• Use Triprolidine Suspension with caution in the ELDERLY; they may be more sensitive to its effects, especially dizziness, sedation, and lightheadedness upon standing.


• Triprolidine Suspension should be used with extreme caution in CHILDREN younger than 2 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 Triprolidine Suspension while you are pregnant. Triprolidine Suspension is found in breast milk. Do not breast-feed while you are taking Triprolidine Suspension.

Possible side effects of Triprolidine Suspension:

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:

Dizziness; drowsiness; dry mouth, throat, and nose; excitability; loss of appetite; thickening of mucus in nose or throat.

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); convulsions; decreased alertness; fast heartbeat or pounding in the chest; hallucinations; tremor; trouble urinating; wheezing.

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: Triprolidine 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 ( http://www.aapcc.org), or emergency room immediately. Symptoms may include coma; excitement; hallucinations; loss of consciousness; muscle twitching; seizures; tremor; weakness.

Proper storage of Triprolidine Suspension:

Store Triprolidine Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Triprolidine Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Triprolidine Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Triprolidine Suspension is 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 Triprolidine Suspension. 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 Triprolidine resources

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

Compare Triprolidine with other medications

• Allergic Urticaria
• Allergies
• Conjunctivitis, Allergic
• Eye Redness/Itching
• Hay Fever
• Rhinorrhea

APC-Dimenhydrinate

APC-Dimenhydrinate may be available in the countries listed below.

Ingredient matches for APC-Dimenhydrinate

Dimenhydrinate

Dimenhydrinate is reported as an ingredient of APC-Dimenhydrinate in the following countries:

• Canada

International Drug Name Search

Truvada

Generic Name: emtricitabine and tenofovir disoproxil fumarate

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of Truvada, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].

Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].

Indications and Usage for Truvada

 Truvada®, a combination of EMTRIVA® and VIREAD®, is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

The following points should be considered when initiating therapy with Truvada for the treatment of HIV-1 infection:

• It is not recommended that Truvada be used as a component of a triple nucleoside regimen.


• Truvada should not be coadministered with ATRIPLA®, EMTRIVA, VIREAD or lamivudine-containing products [See Warnings and Precautions (5.4)].


• In treatment experienced patients, the use of Truvada should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)].

Truvada Dosage and Administration

Recommended Dose

 The dose of Truvada for adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Dose Adjustment for Renal Impairment

Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment [see EMTRIVA or VIREAD Package Insert]. Therefore, the dosing interval of Truvada should be adjusted in patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].

Table 1 Dosage Adjustment for Patients with Altered Creatinine Clearance

	Creatinine Clearance (mL/min)*
	≥50	30–49	<30 (Including Patients Requiring Hemodialysis)
* Calculated using ideal (lean) body weight
Recommended Dosing Interval	Every 24 hours	Every 48 hours	Truvada should not be administered.

 No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.

Dosage Forms and Strengths

Truvada is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side and with "701" on the other side.

Contraindications

None.

Warnings and Precautions

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of Truvada, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Truvada should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Truvada is not approved for the treatment of chronic HBV infection and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Truvada. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Truvada. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.

Dosing interval adjustment of Truvada and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min, [See Dosage and Administration (2.2)]. No safety or efficacy data are available in patients with renal impairment who received Truvada using these dosing guidelines, so the potential benefit of Truvada therapy should be assessed against the potential risk of renal toxicity. Truvada should not be administered to patients with creatinine clearance below 30 mL/min or patients requiring hemodialysis.

Truvada should be avoided with concurrent or recent use of a nephrotoxic agent.

Coadministration with Other Products

Truvada is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. Truvada should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, Truvada should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

Truvada should not be administered with HEPSERA® (adefovir dipivoxil).

Decreases in Bone Mineral Density

 Assessment of bone mineral density (BMD) should be considered for HIV-1 infected adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive adult subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD.

 In a clinical trial of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this trial, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Truvada. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Early Virologic Failure

Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].


• Severe Acute Exacerbations of hepatitis B [See Boxed Warning, Warnings and Precautions (5.2)].


• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].


• Decreases in Bone Mineral Density [See Warnings and Precautions (5.5)].


• Immune Reconstitution Syndrome [See Warnings and Precautions (5.7)].

Adverse Reactions from Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Adult Subjects

The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 2 for the frequency of treatment-emergent adverse reactions (Grade 2–4) occurring in greater than or equal to 5% of subjects treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate in this trial.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naive subjects receiving VIREAD and/or EMTRIVA (Table 2).

Table 2 Selected Treatment-Emergent Adverse Reactions* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)

	FTC + TDF + EFV†	AZT/3TC + EFV
	N=257	N=254
* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † From Weeks 96 to 144 of the trial, subjects received Truvada with efavirenz in place of VIREAD + EMTRIVA with efavirenz. ‡ Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.
Gastrointestinal Disorder
Diarrhea	9%	5%
Nausea	9%	7%
Vomiting	2%	5%
General Disorders and Administration Site Condition
Fatigue	9%	8%
Infections and Infestations
Sinusitis	8%	4%
Upper respiratory tract infections	8%	5%
Nasopharyngitis	5%	3%
Nervous System Disorders
Headache	6%	5%
Dizziness	8%	7%
Psychiatric Disorders
Depression	9%	7%
Insomnia	5%	7%
Skin and Subcutaneous Tissue Disorders
Rash event‡	7%	9%

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 3).

Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks)

	FTC + TDF + EFV*	AZT/3TC + EFV
	N=257	N=254
* From Weeks 96 to 144 of the trial, subjects received Truvada with efavirenz in place of VIREAD + EMTRIVA with efavirenz.
Any ≥ Grade 3 Laboratory Abnormality	30%	26%
Fasting Cholesterol (>240 mg/dL)	22%	24%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	9%	7%
Serum Amylase (>175 U/L)	8%	4%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%
ALT (M: >215 U/L) (F: >170 U/L)	2%	3%
Hemoglobin (<8.0 mg/dL)	0%	4%
Hyperglycemia (>250 mg/dL)	2%	1%
Hematuria (>75 RBC/HPF)	3%	2%
Glycosuria (≥3+)	<1%	1%
Neutrophils (<750/mm3)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.

In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 laboratory abnormalities of increased bilirubin (>2.5 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.

Clinical Trials in Pediatric Subjects 12 Years of Age and Older

Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information.

Tenofovir Disoproxil Fumarate: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See Warnings and Precautions (5.5)].

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Drug Interactions

No drug interaction trials have been conducted using Truvada tablets. Drug interaction trials have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of Truvada. This section describes clinically relevant drug interactions observed with emtricitabine and tenofovir disoproxil fumarate [See Clinical Pharmacology (12.3)].

Didanosine

Coadministration of Truvada and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with Truvada. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, Truvada and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with Truvada should be under fasted conditions.

Atazanavir

Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving atazanavir and Truvada should be monitored for Truvada-associated adverse reactions. Truvada should be discontinued in patients who develop Truvada-associated adverse reactions.

Tenofovir decreases the AUC and Cmin of atazanavir [See Clinical Pharmacology (12.3)]. When coadministered with Truvada, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with Truvada.

Lopinavir/Ritonavir

Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and Truvada should be monitored for Truvada-associated adverse reactions. Truvada should be discontinued in patients who develop Truvada-associated adverse reactions.

Drugs Affecting Renal Function

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [See Clinical Pharmacology (12.3)]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of Truvada with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.

Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, Truvada should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Truvada, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Truvada.

Pediatric Use

Truvada should only be administered to pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) because it is a fixed-dose combination tablet containing a component, VIREAD, for which safety and efficacy have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb) [See Warnings and Precautions (5.5), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Geriatric Use

Clinical trials of EMTRIVA or VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients with Impaired Renal Function

It is recommended that the dosing interval for Truvada be modified in patients with creatinine clearance 30–49 mL/min. Truvada should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

Overdosage

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology trials single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one trial, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Truvada Description

Truvada tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

Truvada tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Truvada - Clinical Pharmacology

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information.

Mechanism of Action

Truvada is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)].

Pharmacokinetics

Truvada: One Truvada tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 4. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 4. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 4 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults*

	Emtricitabine	Tenofovir
* NC = Not calculated † Median (range) ‡ Mean (± SD) § Data presented as steady state values.
Fasted Oral Bioavailability† (%)	92 (83.1–106.4)	25 (NC–45.0)
Plasma Terminal Elimination Half-Life† (hr)	10 (7.4–18.0)	17 (12.0–25.7)
Cmax‡ (µg/mL)	1.8 ± 0.72§	0.30 ± 0.09
AUC‡ (µg∙hr/mL)	10.0 ± 3.12§	2.29 ± 0.69
CL/F‡ (mL/min)	302 ± 94	1043 ± 115
CLrenal‡ (mL/min)	213 ± 89	243 ± 33

Effects of Food on Oral Absorption

Truvada may be administered with or without food. Administration of Truvada following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when Truvada was administered with either a high fat or a light meal.

Special Populations

Race

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Gender

Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

Truvada should not be administered to pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb).

Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Geriatric Patients

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Impaired Renal Function

The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0–∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for Truvada be modified in patients with creatinine clearance 30–49 mL/min. Truvada should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of Truvada or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 5 and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in trials conducted in healthy volunteers (see Tables 7 and 8).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug