An-DTPA

Generic Name: technetium tc 99m pentetate (Intravenous route)

tek-NEE-shee-um Tc 99m PEN-te-tate

Commonly used brand name(s)

In the U.S.

• An-DTPA


• MPI DTPA

Available Dosage Forms:

• Kit

Therapeutic Class: Diagnostic Agent, Radiopharmaceutical Imaging

Uses For An-DTPA

Technetium Tc 99m pentetate injection is a radiopharmaceutical. Radiopharmaceuticals are radioactive agents, which may be used to find and treat certain diseases or to study the function of the body's organs.

Technetium Tc 99m pentetate injection is used to help your doctor see an image of your kidneys and assess how well they are working. It is also used to help your doctor see an image of your brain.

This medicine is to be given only by or under the direct supervision of a doctor with specialized training in nuclear medicine.

Before Using An-DTPA

In deciding to use a diagnostic test, any risks of the test must be weighed against the good it will do. This is a decision you and your doctor will make. Also, other things may affect test results. For this test, the following should be considered:

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of technetium Tc 99m pentetate injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of technetium Tc 99m pentetate injection in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Kidney disease—The image quality of the kidney or brain scan may be affected in patients with this condition.

Proper Use of technetium tc 99m pentetate

This section provides information on the proper use of a number of products that contain technetium tc 99m pentetate. It may not be specific to An-DTPA. Please read with care.

A doctor or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins before you have a brain or kidney scan.

You will need to urinate right away and as often as possible for 4 to 6 hours after receiving this medicine. Drink plenty of fluids before and after receiving this medicine so you will pass more urine.

Precautions While Using An-DTPA

It is very important that your doctor check you closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to use it.

While using this medicine, you may be exposed to radiation. Talk with your doctor if you have concerns about this.

An-DTPA Side Effects

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

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

Incidence not known

• Cough


• difficulty with swallowing


• dizziness


• fast heartbeat


• fever


• hives


• itching


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


• shortness of breath


• skin rash


• tightness in the chest


• unusual tiredness or weakness


• wheezing

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

Incidence not known

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

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

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

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

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

Detrusitol 1mg & 2mg film-coated tablets

1. Name Of The Medicinal Product

Detrusitol 1 mg filmcoated tablets

Detrusitol 2 mg filmcoated tablets

2. Qualitative And Quantitative Composition

Each filmcoated tablet contains tolterodine tartrate 1 mg or 2 mg corresponding to 0.68 mg and 1.37 mg tolterodine, respectively

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Filmcoated tablets

The filmcoated tablets are white, round and biconvex. The 1 mg tablet is engraved with arcs above and below the letters TO and the 2 mg tablet is engraved with arcs above and below the letters DT.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome.

4.2 Posology And Method Of Administration

Adults (including elderly):

The recommended dose is 2 mg twice daily except in patients with impaired liver function or severely impaired renal function (GFR<30 ml/min) for whom the recommended dose is 1 mg twice daily (see section 4.4). In case of troublesome side effects the dose may be reduced from 2 mg to 1 mg twice daily.

The effect of treatment should be re-evaluated after 2-3 months (see section 5.1).

Paediatric patients:

Efficacy of Detrusitol has not been demonstrated in children (See section 5.1). Therefore, Detrusitol is not recommended for children.

4.3 Contraindications

Tolterodine is contraindicated in patients with

- Urinary retention

- Uncontrolled narrow angle glaucoma

- Myasthenia gravis

- Known hypersensitivity to tolterodine or excipients

- Severe ulcerative colitis

- Toxic megacolon

4.4 Special Warnings And Precautions For Use

Tolterodine shall be used with caution in patients with

- Significant bladder outlet obstruction at risk of urinary retention

- Gastrointestinal obstructive disorders, e.g. pyloric stenosis

- Renal impairement (see section 4.2)

- Hepatic disease. (see section 4.2 and 5.2)

- Autonomic neuropathy

- Hiatus hernia

- Risk for decreased gastrointestinal motility

Multiple oral total daily doses of immediate release 4 mg (therapeutic) and 8 mg (supratherapeutic) tolterodine have been shown to prolong the QTc interval (see section 5.1). The clinical relevance of these findings is unclear and will depend on individual patient risk factors and susceptibilities present.

Tolterodine should be used with caution in patients with risk factors for QT-prolongation including:

- Congenital or documented acquired QT prolongation

- Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia

- Bradycardia

- Relevant pre-existing cardiac diseases (i.e. cardiomyopathy, myocardial ischaemia, arrhythmia, congestive heart failure)

- Concomitant administration of drugs known to prolong QT-interval including Class IA (e. g. quinidine, procainamide) and Class III (e. g. amiodarone, sotalol) anti-arrhythmics

This especially holds true when taking potent CYP3A4 inhibitors (see section 5.1).

Concomitant treatment with potent CYP3A4 inhibitors should be avoided (see section 4.5, Interactions).

As with all treatments for symptoms of urgency and urge incontinence, organic reasons for urge and frequency should be considered before treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant systemic medication with potent CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin and clarithromycin), antifungal agents (e.g. ketoconazole and itraconazole) and antiproteases is not recommended due to increased serum concentrations of tolterodine in poor CYP2D6 metabolisers with (subsequent) risk of overdosage (see section 4.4).

Concomitant medication with other drugs that possess antimuscarinic properties may result in more pronounced therapeutic effect and side-effects. Conversely, the therapeutic effect of tolterodine may be reduced by concomitant administration of muscarinic cholinergic receptor agonists.

The effect of prokinetics like metoclopramide and cisapride may be decreased by tolterodine.

Concomitant treatment with fluoxetine (a potent CYP2D6 inhibitor) does not result in a clinically significant interaction since tolterodine and its CYP2D6-dependent metabolite, 5-hydroxymethyl tolterodine are equipotent.

Drug interaction studies have shown no interactions with warfarin or combined oral contraceptives (ethinyl estradiol/levonorgestrel).

A clinical study has indicated that tolterodine is not a metabolic inhibitor of CYP2D6, 2C19, 2C9, 3A4 or 1A2. Therefore an increase of plasma levels of drugs metabolised by these isoenzymes is not expected when dosed in combination with tolterodine.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of tolterodine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Consequently, Detrusitol is not recommended during pregnancy.

Lactation

No data concerning the excretion of tolterodine into human milk are available. Tolterodine should be avoided during lactation.

4.7 Effects On Ability To Drive And Use Machines

Since this drug may cause accommodation disturbances and influence reaction time, the ability to drive and use machines may be negatively affected.

4.8 Undesirable Effects

Due to the pharmacological effect of tolterodine it may cause mild to moderate antimuscarinic effects, like dryness of the mouth, dyspepsia and dry eyes.

The table below reflects the data obtained with Detrusitol in clinical trials and from postmarketing experience. The most commonly reported adverse reaction was dry mouth, which occurred in 35% of patients treated with Detrusitol tablets and in 10% of placebo treated patients. Headaches were also reported very commonly and occurred in 10.1% of patients treated with Detrusitol tablets and in 7.4% of placebo treated patients.

	Very Common (	Common (	Uncommon (	Not known (cannot be estimated from the available data)
Infections and infestations		Bronchitis
Immune system disorders			Hypersensitivity not otherwise specified	Anaphylactoid reactions
Psychiatric disorders			Nervousness	Confusion , hallucinations, disorientation
Nervous system disorders	Headaches	Dizziness, somnolence, paresthesia	Memory impairment
Eye disorders		Dry eyes, abnormal vision including abnormal accommodation
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Palpitations	Tachycardia, cardiac failure, arrhythmia
Vascular disorders				Flushing
Gastrointestinal disorders	Dry mouth	Dyspepsia, constipation, abdominal pain, flatulence, vomiting, diarrhoea	Gastroesophageal reflux
Skin and subcutaneous tissue disorders		Dry skin		Angioedema
Renal and urinary disorders		Dysuria, urinary retention
General disorders		Fatigue, chest pain, peripheral oedema
Investigations		Increased weight

Cases of aggravation of symptoms of dementia (e.g. confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

Paediatric patients

In two paediatric phase III randomised, placebo-controlled, double-blind studies conducted over 12 weeks where a total of 710 paediatric patients were recruited, the proportion of patients with urinary tract infections, diarrhoea and abnormal behaviour was higher in patients treated with tolterodine than placebo (urinary tract infection: tolterodine 6.8 %, placebo 3.6 %; diarrhoea: tolterodine 3.3 %, placebo 0.9 %; abnormal behaviour: tolterodine 1.6 %, placebo 0.4 %). (See section 5.1)

4.9 Overdose

The highest dose given to human volunteers of tolterodine L-tartrate is 12.8 mg as single dose. The most severe adverse events observed were accommodation disturbances and micturition difficulties.

In the event of tolterodine overdose, treat with gastric lavage and give activated charcoal. Treat symptoms as follows:

• Severe central anticholinergic effects (e.g. hallucinations, severe excitation): treat with physostigmine

• Convulsions or pronounced excitation: treat with benzodiazepines

• Respiratory insufficiency: treat with artificial respiration

• Tachycardia: treat with beta-blockers

• Urinary retention: treat with catheterization

• Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room

An increase in QT interval was observed at a total daily dose of 8 mg immediate release tolterodine (twice the recommended daily dose of the immediate release formulation and equivalent to three times the peak exposure of the prolonged release capsule formulation) administered over four days. In the event of tolterodine overdose, standard supportive measures for managing QT prolongation should be adopted.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Urinary antispasmodics

ATC code: G04B D07

Tolterodine is a competitive, specific muscarinic receptor antagonist with a selectivity for the urinary bladder over salivary glands in vivo. One of the tolterodine metabolites (5-hydroxymethyl derivative) exhibits a pharmacological profile similar to that of the parent compound. In extensive metabolisers this metabolite contributes significantly to the therapeutic effect (see 5.2).

Effect of the treatment can be expected within 4 weeks.

Effect of treatment with Detrusitol 2 mg twice daily after 4 and 12 weeks, respectively, compared with placebo (pooled data). Absolute change and percentage change relative to baseline.

Variable	4-week studies	12-week studies
	Detrusitol 2 mg b.i.d.	Placebo	Statistical significance vs. placebo	Detrusitol 2 mg b.i.d.	Placebo	Statistical significance vs. placebo
Number of micturitions per 24 hours	-1.6 (-14%) n=392	-0.9 (-8%) n=189	*	-2.3 (-20%) n=354	-1.4 (-12%) n=176	**
Number of incontinence episodes per 24 hours	-1.3 (-38%) n=288	-1.0 (-26%) n=151	n.s.	-1.6 (-47%) n=299	-1.1 (-32%) n=145	*
Mean volume voided per micturition (ml)	+25 (+17%) n=385	+12 (+8%) n=185	***	+35 (+22%) n=354	+10 (+6%) n=176	***
Number of patients with no or minimal bladder problems after treatment (%)	16% n=394	7% n=190	**	19% n=356	15% n=177	n.s.

n.s.=not significant; *=p<0.05; **= p<0.01; ***= p<0.001

The effect of tolterodine was evaluated in patients, examined with urodynamic assessment at baseline and, depending on the urodynamic result, they were allocated to a urodynamic positive (motor urgency) or a urodynamic negative (sensory urgency) group. Within each group, the patients were randomised to receive either tolterodine or placebo. The study could not provide convincing evidence that tolterodine had effects over placebo in patients with sensory urgency.

The clinical effects of tolterodine on QT interval were studied in ECGs obtained from over 600 treated patients, including the elderly and patients with pre-existing cardiovascular disease. The changes in QT intervals did not significantly differ between placebo and treatment groups.

The effect of tolterodine on QT-prolongation was investigated further in 48 healthy male and female volunteers aged 18 – 55 years. Subjects were administered 2 mg BID and 4 mg BID tolterodine as the immediate release formulations. The results (Fridericia corrected) at peak tolterodine concentration (1 hour) showed mean QTc interval increases of 5.0 and 11.8 msec for tolterodine doses of 2 mg BID 4 mg BID respectively and 19.3 msec for moxifloxacin (400mg) which was used as an active internal control. A pharmacokinetic/pharmacodynamic model estimated that QTc interval increases in poor metabolisers (devoid of CYP2D6) treated with tolterodine 2mg BID are comparable to those observed in extensive metabolisers receiving 4mg BID. At both doses of tolterodine, no subject, irrespective of their metabolic profile, exceeded 500 msec for absolute QTcF or 60 msec for change from baseline that are considered thresholds of particular concern. The 4mg BID dose corresponds to a peak exposure (C_max) of three times that obtained with the highest therapeutic dose of Detrusitol XL capsules.

Paediatric patients

Efficacy in the paediatric population has not been demonstrated. Two paediatric phase 3 randomised, placebo-controlled, double-blind 12 week studies were conducted using tolterodine extended release capsules. A total of 710 paediatric patients (486 on tolterodine and 224 on placebo) aged 5-10 years with urinary frequency and urge urinary incontinence were studied. No significant difference between the two groups was observed in either study with regard to change from baseline in total number of incontinence episodes/week. (See section 4.8)

5.2 Pharmacokinetic Properties

Pharmacokinetic characteristics specific for this formulation:Tolterodine is rapidly absorbed. Both tolterodine and the 5-hydroxymethyl metabolite reach maximal serum concentrations 1-3 hours after dose. The half-life for tolterodine given as the tablet is 2-3 hours in extensive and about 10 hours in poor metabolisers (devoid of CYP2D6). Steady state concentrations are reached within 2 days after administration of the tablets.

Food does not influence the exposure to the unbound tolterodine and the active 5-hydroxymethyl metabolite in extensive metabolisers, although the tolterodine levels increase when taken with food. Clinically relevant changes are likewise not expected in poor metabolisers.

Absorption: After oral administration tolterodine is subject to CYP2D6 catalysed first-pass metabolism in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically equipotent metabolite.

The absolute bioavailability of tolterodine is 17 % in extensive metabolisers, the majority of the patients, and 65% in poor metabolisers (devoid of CYP2D6).

Distribution: Tolterodine and the 5-hydroxymethyl metabolite bind primarily to orosomucoid. The unbound fractions are 3.7% and 36%, respectively. The volume of distribution of tolterodine is 113 l.

Elimination: Tolterodine is extensively metabolised by the liver following oral dosing. The primary metabolic route is mediated by the polymorphic enzyme CYP2D6 and leads to the formation of the 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51 % and 29 % of the metabolites recovered in the urine, respectively. A subset (about 7%) of the population is devoid of CYP2D6 activity. The identified pathway of metabolism for these individuals (poor metabolisers) is dealkylation via CYP3A4 to N-dealkylated tolterodine, which does not contribute to the clinical effect. The remainder of the population is referred to as extensive metabolisers. The systemic clearance of tolterodine in extensive metabolisers is about 30 L/h. In poor metabolisers the reduced clearance leads to significantly higher serum concentrations of tolterodine (about 7-fold) and negligible concentrations of the 5-hydroxymethyl metabolite are observed.

The 5-hydroxymethyl metabolite is pharmacologically active and equipotent with tolterodine. Because of the differences in the protein-binding characteristics of tolterodine and the 5-hydroxymethyl metabolite, the exposure (AUC) of unbound tolterodine in poor metabolisers is similar to the combined exposure of unbound tolterodine and the 5-hydroxymethyl metabolite in patients with CYP2D6 activity given the same dosage regimen. The safety, tolerability and clinical response are similar irrespective of phenotype.

The excretion of radioactivity after administration of [¹⁴C]-tolterodine is about 77% in urine and 17% in faeces. Less than 1% of the dose is recovered as unchanged drug, and about 4% as the 5-hydroxymethyl metabolite. The carboxylated metabolite and the corresponding dealkylated metabolite account for about 51% and 29% of the urinary recovery, respectively.

The pharmacokinetics is linear in the therapeutic dosage range.

Specific patient groups:

Impaired liver function: About 2-fold higher exposure of unbound tolterodine and the 5-hydroxymethyl metabolite is found in subjects with liver cirrhosis (see section 4.2 and 4.4).

Impaired renal function: The mean exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is doubled in patients with severe renal impairment (inulin clearance GFR

Paediatric patients

The exposure of the active moiety per mg dose is similar in adults and adolescents. The mean exposure of the active moiety per mg dose is approximately two-fold higher in children between 5-10 years than in adults (See sections 4.2 and 5.1).

5.3 Preclinical Safety Data

In toxicity, genotoxicity, carcinogenicity and safety pharmacology studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the drug.

Reproduction studies have been performed in mice and rabbits.

In mice, there was no effect of tolterodine on fertility or reproductive function. Tolterodine produced embryo death and malformations at plasma exposures (C_max or AUC) 20 or 7 times higher than those seen in treated humans.

In rabbits, no malformative effect was seen, but the studies were conducted at 20 or 3 times higher plasma exposure (C_max or AUC) than those expected in treated humans.

Tolterodine, as well as its active human metabolites prolong action potential duration (90% repolarisation) in canine purkinje fibres (14 - 75 times therapeutic levels) and block the K+-current in cloned human ether-a-go-go-related gene (hERG) channels (0.5 – 26.1 times therapeutic levels). In dogs prolongation of the QT interval has been observed after application of tolterodine and its human metabolites (3.1 – 61.0 times therapeutic levels). The clinical relevance of these findings is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Cellulose, microcrystalline

Calcium hydrogen phosphate dihydrate

Sodium starch glycollate (Type B)

Magnesium stearate

Colloidal anhydrous silica

Film coating:

Coating granules containing

Hypromellose

Cellulose, microcrystalline

Stearic acid

Titanium dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

No special precautions for storage

6.5 Nature And Contents Of Container

Tablets are packed in either blister package made of PVC/PVDC and aluminium foil with a heat seal coating of PVDC or HDPE bottles with LDPE closures.

Pack sizes:

Detrusitol tablets are available in blisters of 2x10, 3x10, 5x10 and 10x10 tablets, 1x14, 2x14 and 4x14 tablets, 280 and 560 tablets and in bottles of 60 and 500 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Pharmacia Ltd

Ramsgate Road

Sandwich

Kent

CT 13 9NJ

UK

8. Marketing Authorisation Number(S)

PL 00032/0222

PL 00032/0223

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd February 1998/ 23^rd March 2006

10. Date Of Revision Of The Text

February 2009

11 Legal category

POM

Ref: DT A 7_0

Campral

Generic Name: acamprosate (a KAM proe sate)

Brand Names: Campral

What is acamprosate?

Acamprosate affects chemicals in the brain that may become unbalanced in a person who is addicted to alcohol. Acamprosate works by restoring this chemical balance in the brain in an alcohol-dependent person who has recently quit drinking.

Acamprosate is used to help a person who has recently quit drinking alcohol continue to choose not to drink (remain abstinent from alcohol). It is used together with behavior modification and counseling support to help you stop drinking.

Acamprosate is not likely to be helpful to a person who has not already quit drinking or undergone detoxification. It may not be helpful to a person who is also addicted to other substances besides alcohol.

Acamprosate may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about acamprosate?

You should not use this medication if you are allergic to acamprosate, or if you have severe kidney disease.

Acamprosate will not treat or prevent alcohol withdrawal symptoms.

Before you take acamprosate, tell your doctor if you have any type of kidney problem. You may need a dose adjustment or special tests to safely use this medication.

You may have thoughts about suicide while you are taking acamprosate. Tell your doctor if you feel depressed or have any suicidal thoughts or actions during treatment.

Your family or other caregivers should also be alert to changes in your mood or behavior. Make sure your caregivers know how to contact your doctor in case you have mood changes or suicidal thoughts or actions.

Acamprosate 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. Take this medication for the full prescribed length of time, even if you relapse and drink alcohol. While you are taking acamprosate, tell your doctor about any alcoholic drinks you consume, no matter how many.

What should I discuss with my healthcare provider before taking acamprosate?

You should not use this medication if you are allergic to acamprosate, or if you have severe kidney disease.

Acamprosate will not treat or prevent alcohol withdrawal symptoms.

Before you take acamprosate, tell your doctor if you have any type of kidney problem. You may need a dose adjustment or special tests to safely use this medication.

FDA pregnancy category C. It is not known whether acamprosate is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether acamprosate passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. You may have thoughts about suicide while you are taking acamprosate. Tell your doctor if you feel depressed or have any suicidal thoughts or actions during treatment.

Your family or other caregivers should also be alert to changes in your mood or behavior. Make sure your caregivers know how to contact your doctor in case you have mood changes or suicidal thoughts or actions.

How should I take acamprosate?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Acamprosate treatment should be started as soon as possible after you have quit drinking.

Take this medicine with water.

Acamprosate is usually taken 3 times daily, and may be taken with or without food. If you regularly eat 3 meals per day, it may help you remember to take your acamprosate if you take a dose with each meal. Follow your doctor's instructions.

Acamprosate is only part of a complete program of treatment that also includes counseling support and continued abstinence from alcohol.

Take this medication for the full prescribed length of time, even if you relapse and drink alcohol. While you are taking acamprosate, tell your doctor about any alcoholic drinks you consume, no matter how many.

It is important to use acamprosate regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store acamprosate at room temperature away from moisture and heat.

See also: Campral dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. 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 can cause diarrhea but is not expected to produce serious side effects.

What should I avoid while taking acamprosate?

Acamprosate 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.

Acamprosate 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. Call your doctor at once if you have a serious side effects such as:

• 
  

  mood or behavior changes;

  
  


• 
  

  thoughts about hurting yourself;

  
  


• 
  

  severe anxiety or depression;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  fast or pounding heartbeats;

  
  


• 
  

  swelling, weight gain, feeling short of breath;

  
  


• 
  

  confusion, increased thirst; or

  
  


• 
  

  urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  nausea, vomiting, stomach pain, loss of appetite;

  
  


• 
  

  constipation, diarrhea;

  
  


• 
  

  headache, dizziness, drowsiness;

  
  


• 
  

  vision problems;

  
  


• 
  

  problems with memory or thinking;

  
  


• 
  

  weakness, cold or flu-like symptoms;

  
  


• 
  

  back pain, joint or muscle pain;

  
  


• 
  

  dry mouth, decreased or distorted sense of taste;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  impotence, loss of interest in sex;

  
  


• 
  

  sweating, mild skin rash; or

  
  


• 
  

  numbness or tingly feeling.

  
  

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

What other drugs will affect acamprosate?

There may be other drugs that can interact with acamprosate. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Campral resources

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

• Campral Prescribing Information (FDA)


• Campral Monograph (AHFS DI)


• Campral Advanced Consumer (Micromedex) - Includes Dosage Information


• Campral MedFacts Consumer Leaflet (Wolters Kluwer)


• Campral Consumer Overview

Compare Campral with other medications

• Alcohol Dependence

Where can I get more information?

• Your pharmacist can provide more information about acamprosate.

See also: Campral side effects (in more detail)

Celsentri 150mg film-coated tablets

1. Name Of The Medicinal Product

CELSENTRI 150 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 150 mg of maraviroc.

Excipients

Each 150 mg film-coated tablet contains 0.84 mg of soya lecithin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Blue, biconvex, oval film-coated tablets debossed with “Pfizer” on one side and “MVC 150” on the other

4. Clinical Particulars

4.1 Therapeutic Indications

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable (see section 4.2).

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients (see section 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection method on a newly drawn blood sample. The Monogram Trofile assay was used in the clinical studies of CELSENTRI (see sections 4.4 and 5.1). Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be safely predicted by treatment history and assessment of stored samples.

There are currently no data regarding the reuse of CELSENTRI in patients that currently have only CCR5-tropic HIV-1 detectable, but have a history of failure on CELSENTRI (or other CCR5 antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch from a medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressed patients. Alternative treatment options should be considered.

Adults: the recommended dose of CELSENTRI is 150 mg, 300 mg or 600 mg twice daily depending on interactions with co-administered antiretroviral therapy and other medicinal products (see Table 2 in Section 4.5). CELSENTRI can be taken with or without food.

Children: CELSENTRI is not recommended for use in children due to lack of data on safety, efficacy and pharmacokinetics (see section 5.2).

Elderly: there is limited experience in patients>65 years of age (see section 5.2), therefore CELSENTRI should be used with caution in this population.

Renal impairment: dosage adjustment is only recommended in patients with renal impairment who are receiving potent CYP3A4 inhibitors such as:

• protease inhibitors (except tipranavir/ritonavir)

• ketoconazole, itraconazole, clarithromycin, telithromycin.

CELSENTRI should be used with caution in patients with severe renal impairment (CLcr < 30mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).

The dose and dosing interval for CELSENTRI should be modified in renally impaired patients (CLcr <80 mL/min), including patients with end stage renal disease (ESRD) requiring dialysis (Table 1 below). These dosing recommendations are based on data from a renal impairment study (see section 5.2) in addition to modelling of pharmacokinetic data in subjects with varying degrees of renal impairment.

Table 1. Dose and interval adjustments for patients with renal impairment

Recommended CELSENTRI dose interval	Creatinine clearance <80 mL/min
If administered without potent CYP3A4 inhibitors or if co-administered with tipranavir/ritonavir	No dose interval adjustment required
If co-administered with fosamprenavir/ritonavir	CELSENTRI 150 mg every 12 hours
If co-administered with potent CYP3A4 inhibitors, e.g. saquinavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, atazanavir/ritonavir, ketoconazole	CELSENTRI 150 mg every 24 hours

Hepatic impairment: limited data are available in patients with hepatic impairment, therefore CELSENTRI should be used with caution in this population (see sections 4.4 and 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to peanut or soya or to any of the excipients.

4.4 Special Warnings And Precautions For Use

CELSENTRI should be taken as part of an antiretroviral combination regimen. CELSENTRI should optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section 5.1).

CELSENTRI should only be used when only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) as determined by an adequately validated and sensitive detection method (see sections 4.1, 4.2 and 5.1). The Monogram Trofile assay was used in the clinical studies of CELSENTRI. Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be predicted by treatment history or assessment of stored samples.

Changes in viral tropism occur over time in HIV-1 infected patients. Therefore there is a need to start therapy shortly after a tropism test.

Background resistance to other classes of antiretrovirals have been shown to be similar in previously undetected CXCR4-tropic virus of the minor viral population, as that found in CCR5-tropic virus.

CELSENTRI is not recommended to be used in treatment-naïve patients based on the results of a clinical study in this population (see section 5.1).

Dose adjustment: physicians should ensure that appropriate dose adjustment of CELSENTRI is made when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers since maraviroc concentrations and its therapeutic effects may be affected (see sections 4.2 and 4.5). Please also refer to the respective Summary of Product Characteristics of the other antiretroviral medicinal products used in the combination.

Information for patients: patients should be advised that antiretroviral therapies including CELSENTRI have not been shown to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. They should continue to use appropriate precautions. Patients should also be informed that CELSENTRI is not a cure for HIV-1 infection.

Postural hypotension: when CELSENTRI was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo (approximately 0.5%). Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Potential effect on immunity: CCR5 antagonists could potentially impair the immune response to certain infections. This should be taken into consideration when treating infections such as active tuberculosis and invasive fungal infections. The incidence of AIDS-defining infections was similar between CELSENTRI and placebo arms in the pivotal studies.

Cardiovascular safety: limited data exist with the use of CELSENTRI in patients with severe cardiovascular disease, therefore special caution should be exercised when treating these patients with CELSENTRI. In the pivotal studies of treatment-experienced patients (MOTIVATE) coronary heart disease events was more common in patients treated with CELSENTRI than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients (MERIT) such events occurred at a similarly low rate with CELSENTRI and control (efavirenz).

When CELSENTRI was administered to healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo/comparator. Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Immune reconstitution syndrome: in HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment initiated when necessary.

Osteonecrosis: although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatic safety: the safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders.

A case of possible CELSENTRI-induced hepatotoxicity with allergic features has been reported in a study in healthy volunteers. In addition, an increase in hepatic adverse reactions with CELSENTRI was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups (see section 4.8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.

Discontinuation of CELSENTRI should be considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophila or elevated IgE).

Since there are very limited data in patients with hepatitis B/C co-infection, special caution should be exercised when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer also to the relevant product information for these medicinal products.

There is limited experience in patients with reduced hepatic function, therefore CELSENTRI should be used with caution in this population (see sections 4.2 and 5.2).

Renal impairment: An increased risk of postural hypotension may occur in patients with severe renal insufficiency who are treated with boosted protease inhibitors (PIs) and CELSENTRI. This risk is due to potential increases in maraviroc maximum concentrations when CELSENTRI is co-administered with boosted PIs in these patients. The risk of postural hypotension is highest when CELSENTRI is co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ ritonavir, darunavir/ ritonavir, lopinavir/ ritonavir). Patients with impaired renal function may frequently have cardiovascular co-morbidities, and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. No studies have been performed in subjects with severe renal impairment co-treated with potent CYP3A4 inhibitors. Dose adjustments are based on modelling and simulations (see sections 4.2, 4.5 and 5.2)

Soya lecithin: CELSENTRI contains soya lecithin. If a patient is hypersensitive to peanut or soya, CELSENTRI should not be used.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Maraviroc is a substrate of cytochrome P450 CYP3A4. Co-administration of CELSENTRI with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of CELSENTRI with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI is recommended when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 2).

Studies in human liver microsomes and recombinant enzyme systems have shown that maraviroc does not inhibit any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low.

Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. As both passive and active processes are involved, there is the potential for competition for elimination with other renally eliminated active substances. However, co-administration of CELSENTRI with tenofovir (substrate for renal elimination) and Cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of CELSENTRI with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.

Table 2. Interactions and dose recommendations with other medical products

Medicinal product by therapeutic areas (dose of CELSENTRI used in study)	Effects on drug levels Geometric mean change if not stated otherwise	Recommendations concerning co-administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Lamivudine 150 mg BID (maraviroc 300 mg BID)	Lamivudine AUC12: ↔ 1.13 Lamivudine Cmax: ↔ 1.16 Maraviroc concentrations not measured, no effect is expected.	No significant interaction seen/expected. CELSENTRI 300 mg twice daily and NRTIs can be co-administered without dose adjustment.
Tenofovir 300 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12: ↔ 1.03 Maraviroc Cmax: ↔ 1.03 Tenofovir concentrations not measured, no effect is expected.
Zidovudine 300 mg BID (maraviroc 300 mg BID)	Zidovudine AUC12: ↔ 0.98 Zidovudine Cmax: ↔ 0.92 Maraviroc concentrations not measured, no effect is expected.
Integrase Inhibitors
Raltegravir 400 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Raltegravir AUC12: Raltegravir Cmax: Raltegravir C12:	No clinically significant interaction seen. CELSENTRI 300 mg twice daily and raltegravir can be co-administered without dose adjustment.
NNRTIs
Efavirenz 600 mg QD (maraviroc 100 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Efavirenz concentrations not measured, no effect is expected.	CELSENTRI dose should be increased to 600 mg twice daily when co-administered with efavirenz in the absence of a potent CYP3A4 inhibitor. For combination with efavirenz + PI, see separate recommendations below.
Etravirine 200 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Etravirine AUC12: ↔ 1.06 Etravirine Cmax: ↔ 1.05 Etravirine C12: ↔ 1.08	Etravirine is only approved for use with boosted protease inhibitors. For combination with etravirine + PI, see below.
Nevirapine 200 mg BID (maraviroc 300 mg Single Dose)	Maraviroc AUC12: ↔ compared to historical controls Maraviroc Cmax: ↑ compared to historical controls Nevirapine concentrations not measured, no effect is expected.	Comparison to exposure in historical controls suggests that CELSENTRI 300 mg twice daily and nevirapine can be co-administered without dose adjustment.
PIs
Atazanavir 400 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12↑ 3.57 Maraviroc Cmax: ↑ 2.09 Atazanavir concentrations not measured, no effect is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with a PI; except in combination with tipranavir/ritonavir or fosamprenavir/ritonavir where the CELSENTRI dose should be 300 mg BID. Maraviroc does not significantly affect PI drug levels.
Atazanavir/ritonavir 300 mg/100 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12↑ 4.88 Maraviroc Cmax: ↑ 2.67 Atazanavir/ritonavir concentrations not measured, no effect is expected.
Lopinavir/ritonavir 400 mg/100 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12↑ 3.95 Maraviroc Cmax: ↑ 1.97 Lopinavir/ritonavir concentrations not measured, no effect is expected.
Saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID)	Maraviroc AUC12↑ 9.77 Maraviroc Cmax: ↑ 4.78 Saquinavir/ritonavir concentrations not measured, no effect is expected.
Darunavir/ritonavir 600 mg/100 mg BID (maraviroc 150 mg BID)	Maraviroc AUC12↑ 4.05 Maraviroc Cmax: ↑ 2.29 Darunavir/ritonavir concentrations were consistent with historical data.
Nelfinavir	Limited data are available for co-administration with nelfinavir. Nelfinavir is a potent CYP3A4 inhibitor and would be expected to increase maraviroc concentrations.
Indinavir	Limited data are available for co-administration with indinavir. Indinavir is a potent CYP3A4 inhibitor. Population PK analysis in phase 3 studies suggests dose reduction of maraviroc when coadministered with indinavir gives appropriate maraviroc exposure.
Fosamprenavir/ritonavir	Fosamprenavir is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.	CELSENTRI 300 mg twice daily and tipranavir/ritonavir or fosamprenavir/ritonavir can be co-administered without dose adjustment.
Tipranavir/ritonavir 500 mg/200 mg BID (maraviroc 150 mg BID)	Maraviroc AUC12↔ 1.02 Maraviroc Cmax: ↔ 0.86 Tipranavir/ritonavir concentrations were consistent with historical data.
NNRTI + PI
Efavirenz 600 mg QD + lopinavir/ritonavir 400mg/100 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12:↑ 2.53 Maraviroc Cmax: ↑ 1.25 Efavirenz, lopinavir/ritonavir concentrations not measured, no effect expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with efavirenz and a PI (except fosamprenavir/ritonavir where the dose should be 300 mg twice daily or tipranavir/ritonavir where the dose should be 600 mg twice daily).
Efavirenz 600 mg QD + saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID)	Maraviroc AUC12:↑ 5.00 Maraviroc Cmax: ↑ 2.26 Efavirenz, saquinavir/ritonavir concentrations not measured, no effect expected.
Efavirenz and atazanavir/ritonavir or darunavir/ritonavir	Not studied. Based on the extent of inhibition by atazanavir/ritonavir or darunavir/ritonavir in the absence of efavirenz, an increased exposure is expected.
Etravirine and darunavir/ritonavir (maraviroc 150 mg BID)	Maraviroc AUC12:↑ 3.10 Maraviroc Cmax: ↑ 1.77 Etravirine AUC12: ↔ 1.00 Etravirine Cmax: ↔ 1.08 Etravirine C12: Darunavir AUC12: Darunavir Cmax: ↔ 0.96 Darunavir C12: Ritonavir AUC12: ↔ 0.93 Ritonavir Cmax: ↔ 1.02 Ritonavir C12:	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with etravirine and a PI (except fosamprenavir/ritonavir where the dose should be 300 mg twice daily).
Etravirine and lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir	Not studied. Based on the extent of inhibition by lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir in the absence of etravirine, an increased exposure is expected.
Antibiotics
Sulphamethoxazole/ Trimethoprim 800 mg/160 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: ↔ 1.11 Maraviroc Cmax: ↔ 1.19 Sulphamethoxazole/trimethoprim concentrations not measured, no effect expected.	CELSENTRI 300 mg twice daily and sulphamethoxazole/trimethoprim can be co-administered without dose adjustment.
Rifampicin 600 mg QD (maraviroc 100 mg BID)	Maraviroc AUC: Maraviroc Cmax: Rifampicin concentrations not measured, no effect expected.	CELSENTRI dose should be increased to 600 mg twice daily when co-administered with rifampicin in the absence of a potent CYP3A4 inhibitor. This dose adjustment has not been studied in HIV patients. See also section 4.4.
Rifampicin + efavirenz	Combination with two inducers has not been studied. There may be a risk of suboptimal levels with risk of loss of virologic response and resistance development.	Concomitant use of CELSENTRI and rifampicin + efavirenz is not recommended.
Rifabutin + PI	Not studied. Rifabutin is considered to be a weaker inducer than rifampicin. When combining rifabutin with protease inhibitors that are potent inhibitors of CYP3A4 a net inhibitory effect on maraviroc is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with rifabutin and a PI (except tipranavir/ritonavir or fosamprenavir/ritonavir where the dose should be 300 mg twice daily) . See also section 4.4.
Clarithromycin, Telithromycin	Not studied, but both are potent CYP3A4 inhibitors and would be expected to increase maraviroc concentrations.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with clarithromycin and telithromycin.
Antifungals
Ketoconazole 400 mg QD (maraviroc 100 mg BID)	Maraviroc AUCtau: ↑ 5.00 Maraviroc Cmax: ↑ 3.38 Ketoconazole concentrations not measured, no effect is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with ketoconazole.
Itraconazole	Not studied. Itraconazole, is a potent CYP3A4 inhibitor and would be expected to increase the exposure of maraviroc.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with itraconazole.
Fluconazole	Fluconazole is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.	CELSENTRI 300 mg twice daily should be administered with caution when co-administered with fluconazole.
Antivirals
HCV agents	Pegylated interferon and ribavirin have not been studied, no interaction is expected.	CELSENTRI 300 mg twice daily and pegylated interferon or ribavirin can be co-administered without dose adjustment.
DRUG ABUSE
Methadone	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and methadone can be coadministered without dose adjustment.
Buprenorphine	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and buprenorphine can be co-administered without dose adjustment.
LIPID LOWERING MEDICINAL PRODUCTS
Statins	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and statins can be co-administered without dose adjustment.
ORAL CONTRACEPTIVES
Ethinylestradiol 30 mcg QD (maraviroc 100 mg BID)	Ethinylestradiol. AUCt:↔ 1.00 Ethinylestradiol. Cmax: ↔ 0.99 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily. and ethinylestradiol can be co-administered without dose adjustment.
Levonorgestrel 150 mcg QD (maraviroc 100 mg BID)	Levonorgestrel. AUC12:↔ 0.98 Levonorgestrel. Cmax: ↔ 1.01 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily and levonorgestrel can be co-administered without dose adjustment.
SEDATIVES
Benzodiazepines
Midazolam 7.5 mg Single Dose (maraviroc 300 mg BID)	Midazolam. AUC: ↔ 1.18 Midazolam. Cmax: ↔ 1.21 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily and midazolam can be co-administered without dose adjustment.
HERBAL PRODUCTS
St John's Wort	Co-administration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels and lead to loss of virologic response and possible resistance to maraviroc.	Concomitant use of maraviroc and St. John's wort (Hypericum Perforatum) or products containing St. John's wort is not recommended.

4.6 Pregnancy And Lactation

No meaningful clinical data on exposure during pregnancy are available. Studies in rats and rabbits showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species (see section 5.3). CELSENTRI should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species. It is not known whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of the potential for HIV transmission as well as any possible undesirable effects in breast-fed infants.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. CELSENTRI may cause dizziness. Patients should be instructed that if they experience dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable Effects

The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who received at least one dose of CELSENTRI during Phase 2b/3 clinical studies. This includes 426 treatment-experienced patients and 360 treatment-naïve patients who received the recommended dose 300 mg twice daily and a further 588 treatment-experienced and treatment-naïve patients who received 300 mg once daily. Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see section 4.4 and 5.1)..

The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (

The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

The following table presents clinically important adverse reactions of moderate intensity or more occurring among patients receiving CELSENTRI in Phase 2b/3 studies at rates greater than rates in the comparator.

Table 3. Clinically important adverse reactions of moderate intensity or more among patients receiving CELSENTRI at rates greater than rates in the comparator

System Organ Class	Adverse Reaction	Frequency
Infections and infestations	Pneumonia, oesophageal candidiasis	uncommon
Neoplasm benign, malignant and unspecified (incl. cysts and polyps)	Bile duct cancer, diffuse large B-cell lymphoma, Hodgkin's disease, metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma	rare
Blood and lymphatic system disorders	Anaemia	common
Pancytopenia, granulocytopenia	rare
Metabolism and nutrition disorders