Osmanil 75 micrograms / h transdermal patch

1. Name Of The Medicinal Product

Osmanil 75 micrograms/h transdermal patch

2. Qualitative And Quantitative Composition

Each patch releases 75 micrograms fentanyl per hour. Each patch of 22.5 cm² contains 12.375 mg fentanyl.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Transdermal patch

Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 75 μg/h“.

4. Clinical Particulars

4.1 Therapeutic Indications

The product is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.

4.2 Posology And Method Of Administration

The dosing is individual and based on the patient's opioid history and takes into account:

- the possible development of tolerance,

- the current general condition,

- the medical status of the patient and

- the degree of severity of the disorder.

The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.

Patients receiving opioid treatment for the first time

For initial dosing patches with a release rate of 12.5 micrograms/hour should be used. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with Osmanil, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe Osmanil after determination of the optimal dosage.

Switching from other opioids

When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:

1. The quantity of analgesics required over the last 24 hours should be determined.

2. The obtained sum should be converted to correspond the oral morphine dosage using Table 1.

3. The corresponding fentanyl dosage should be determined as follows:

a) using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to150:1)

b) using Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)

Table 1: Equianalgesic potency conversion

All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.

	Equianalgesic doses (mg)
Active substance	Parenteral (im)	Oral
Morphine	10	30-40
Hydromorphone	1.5	7.5
Oxycodone	10-15	20-30
Methadone	10	20
Levorphanol	2	4
Oxymorphine	1	10 (rectal)
Diamorphine	5	60
Pethidine	75	-
Codeine	-	200
Buprenorphine	0.4	0.8 (sublingual)
Ketobemidone	10	20-30

Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)

Oral morphine dose (mg/24 h)	Transdermal fentanyl release (micrograms/h)
< 44	12.5
45-134	25
135-224	50
225-314	75
315-404	100
405-494	125
495-584	150
585-674	175
675-764	200
765-854	225
855-944	250
945-1034	275
1035-1124	300

Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)

Oral morphine dose (mg/24 h)	Transdermal fentanyl release (micrograms/h)
< 60	12.5
60-89	25
90-149	50
150-209	75
210-269	100
270-329	125
330-389	150
390-449	175
450-509	200
510-569	225
570-629	250
630-689	275
690-749	300

By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.

The initial evaluation of the maximum analgesic effect of Osmanil should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.

In the first 12 hours after changing to Osmanil the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.

Dose titration and maintenance therapy

The patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. The dose 12.5 micrograms/hour is appropriate for dose titration in the lower dosage area. If analgesia is insufficient at the end of the initial application period, the dose may be increased after 3 days, until the desired effect is obtained for each patient. Additional dose adjustment should normally be performed in 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account.

Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the Osmanil dose exceeds 300 micrograms/hour.

Withdrawal symptoms have been reported when changing from long-term treatment with morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting morphine in low doses.

Changing or ending therapy

If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50 %. As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.

Method of administration

Directly after removal from the pack and the release liner, the patch is applied to a non-hairy area of skin on the upper body (chest, back, upper arm). To remove hair, scissors should be used instead of razors.

Prior to application, the skin should be carefully washed with clean water (no cleaning agents) and thoroughly dried. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.

As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.

Occasionally, additional adhesion of the patch may be required.

If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.

Duration of administration

The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.

If traces of the transdermal patch remain on the skin after its removal, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning, as these may penetrate the skin due to the effect of the patch.

Paediatric population

Method of administration

In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.

Posology

Transdermal fentanyl should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day.

To convert paediatric patients from oral or parenteral opioids to transdermal fentanyl, refer to “Equianalgesic potency conversion” (table 1), and “Recommended transdermal fentanyl dose based upon daily oral morphine dose (table 4).

Table 4: Recommended transdermal fentanyl dose based upon daily oral morphine dose¹

Oral morphine dose (mg/24 h)	Transdermal fentanyl release (micrograms/h)
For paediatric patients2 30-44	For paediatric patients2 12.5
45-134	25

¹In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to transdermal fentanyl

²For conversion to Osmanil doses greater than 25 micrograms/h a conversion ratio of oral morphine to transdermal fentanyl of 150:1 is recommended (see table 2)

For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one Fentanyl 12 micrograms/hour transdermal patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to transdermal fentanyl. The conversion schedule could not be used to convert from transdermal fentanyl into other opioids, as overdose could than occur.

The analgesic effect of the first dose of transdermal fentanyl will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to transdermal fentanyl, the patient should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.

Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of transdermal fentanyl therapy or up-titration of the dose (see also section 4.4).

Dose titration and maintenance

If the analgesic effect of transdermal fentanyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to use more patches. Dose adjustments should be done in 12.5 micrograms/h steps.

Use in elderly patients

Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).

Hepatic and renal impairment

Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Acute or postoperative pain, since dosage titration is not possible during short-term use.

- Severe impairment of the central nervous system.

4.4 Special Warnings And Precautions For Use

The product should be used only as part of an integrated treatment of pain in cases where the patient is adequately assessed medically, socially and psychologically.

Treatment with Osmanil should only be initiated by an experienced physician familiar with the pharmacokinetics of fentanyl transdermal patches and the risk for severe hypoventilation.

After exhibiting a serious adverse reaction a patient should be monitored for 24 hours following removal of a transdermal patch due to the half life of fentanyl (see section 5.2).

In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (e.g. morphine) and to prescribe fentanyl transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.

The transdermal patch should not be cut, since no information is available on the quality, efficacy and safety of such divided patches.

If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of opioid-therapy is recommended.

The most common adverse reactions following administration at usual doses are drowsiness, confusion, nausea, vomiting and constipation. The first of these are transient and their cause should be investigated if symptoms persist. Constipation, on the other hand, does not stop if treatment continues. All of these effects can be expected and should, therefore, be anticipated in order to optimise treatment, especially constipation. Corrective treatment may often be required (see section 4.8).

The concomitant use of barbituric acid derivatives, buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).

Breakthrough pain

Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough pain.

Respiratory depression

As with all potent opioids some patients may experience respiratory depression with Osmanil, and patients must be observed for this effect. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the fentanyl dose is increased. CNS active substances may worsen the respiratory depression (see section 4.5).

In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.

Chronic pulmonary disease

In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse reactions, in such patients opioids may decrease respiratory drive and increase airway resistance.

Drug dependence

Tolerance and physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain.

Increased intracranial pressure

Osmanil should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention such as those with evidence of increased intracranial pressure, impaired consciousness or coma.

Cardiac disease

Opioids may cause hypotension, especially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotension and/or patients with hypovolemia. Fentanyl may produce bradycardia. Osmanil should be administered with caution to patients with bradyarrhythmias.

Impaired liver function

Fentanyl is metabolised to inactive metabolites in the liver, so patients with hepatic disease might have a delayed elimination. Patients with hepatic impairment should be observed carefully and the dose reduced if necessary.

Renal impairment

Less than 10 % of fentanyl is excreted unchanged by the kidneys, and unlike morphine, there are no known active metabolites eliminated by the kidneys. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Patients with fever/external heat

Significant increases in body temperature can potentially increase fentanyl absorption rate. Therefore patients who develop fever should be monitored for opioid adverse reactions. The patch application site should not be exposed to heat from external heat sources, e.g. sauna.

Elderly patients

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. However, studies of fentanyl transdermal patch in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly or cachectic patients should be observed carefully and the dose reduced if necessary.

Paediatric patients

Transdermal fentanyl should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered (see tables 1 and 4 in section 4.2).

Transdermal fentanyl was not studied in infants and toddlers under 2 years of age. Transdermal fentanyl should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Transdermal fentanyl should not be used in infants and toddlers under 2 years of age.

To guard against accidental ingestion by children, use caution when choosing the application site for transdermal fentanyl patches (see section 4.2) and monitor adhesion of the patch closely.

Lactation

As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with Osmanil (see also section 4.6).

Patients with myasthenia gravis

Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients (see also section 4.4).

The concomitant use of other CNS depressants may produce additive depressant effects and hypoventilation, hypotension as well as profound sedation or coma may occur. The CNS depressants mentioned above include:

- opioids

- anxiolytics and tranquilizers

- hypnotics

- general anaesthetics

- phenothiazines

- skeletal muscle relaxants

- sedating antihistamines

- alcoholic beverages

Therefore, the use of any of the above mentioned concomitant medicinal products and active substances require observation of the patient.

MAO-inhibitors have been reported to increase the effect of narcotic analgesics, especially in patients with cardiac failure. Therefore, fentanyl should not be used within 14 days after discontinuation of treatment with MAO-inhibitors.

Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.

Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for four days had no significant effect on the pharmacokinetics of intravenous fentanyl. Increased plasma concentrations were, however, observed in individual subjects. Oral administration of ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of intravenous fentanyl by two thirds and doubled the half-life. Concomitant use of potent CYP3A4-inhibitors (e.g. ritonavir) with transdermally administered fentanyl may result in increased plasma concentrations of fentanyl. This may increase or prolong both the therapeutic effects and the adverse reactions, which may cause severe respiratory depression. In such cases increased care and observation of the patient should be undertaken. Combined use of ritonavir or other potent CYP3A4-inhibitors with transdermal fentanyl is not recommended, unless the patient is carefully observed.

4.6 Pregnancy And Lactation

The safety of fentanyl in pregnancy has not been established. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fentanyl should only be used during pregnancy when clearly necessary.

Long-term treatment during pregnancy may cause withdrawal symptoms in the infant.

It is advised not to use fentanyl during labour and delivery (including caesarean section) since fentanyl passes the placenta and may cause respiratory depression in the new born infant.

Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed infant. Lactation should therefore be discontinued during treatment and for at least 72 hours after the removal of Osmanil (see also section 4.4).

4.7 Effects On Ability To Drive And Use Machines

Osmanil has major influence on the ability to drive and use machines. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers. Patients stabilized on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.

4.8 Undesirable Effects

The following frequencies are used for the description of the occurrence of adverse reactions:

Very common (

The most serious undesirable effect of fentanyl is respiratory depression.

Cardiac disorders

Uncommon: tachycardia, bradycardia.

Rare: arrhythmia.

Nervous system disorders

Very common: headache, dizziness.

Uncommon: tremor, paraesthesia, speech disorder.

Very rare: ataxia, seizures (including clonic and grand mal seizures).

Eye disorders

Very rare: amblyopia.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, hypoventilation.

Very rare: respiratory depression, apnoea.

Gastrointestinal disorders

Very common: nausea, vomiting, constipation.

Common: xerostomia, dyspepsia.

Uncommon: diarrhoea.

Rare: hiccup.

Very rare: painful flatulence, ileus.

Renal and urinary disorders

Uncommon: urinary retention.

Very rare: cystalgia, oliguria.

Skin and subcutaneous tissue disorders

Very common: sweating, pruritus.

Common: skin reactions on the application site.

Uncommon: exanthema, erythema.

Rash, erythema and pruritus will usually disappear within one day after the patch has been removed.

Vascular disorders

Uncommon: hypertension, hypotension.

Rare: vasodilatation.

General disorders and administration site conditions

Rare: oedema, cold feeling.

Immune system disorders

Very rare: anaphylaxis.

Psychiatric disorders

Very common: somnolence.

Common: sedation, nervousness, loss of appetite.

Uncommon: euphoria, amnesia, insomnia, hallucinations, agitation.

Very rare: delusional ideas, states of excitement, asthenia, depression, anxiety, confusion, sexual dysfunction, withdrawal symptoms.

Other undesirable effects

Not known (cannot be estimated from the available data): Long-term use of fentanyl can lead to development of tolerance and physical and psychological dependence. After switching from previously prescribed opioid analgesics to Osmanil or after abrupt discontinuation of therapy patients may show opioid withdrawal symptoms (for instance: nausea, vomiting, diarrhoea, anxiety and shivering).

The adverse event profile in children and adolescents treated with transdermal fentanyl was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with transdermal fentanyl use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea.

4.9 Overdose

Symptoms

The symptoms of fentanyl overdose are an extension of its pharmacological actions, e.g. lethargy, coma, respiratory depression with Cheyne-Stokes respiration and/or cyanosis. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia, hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression, which is the main symptom.

Treatment

For management of respiratory depression immediate countermeasures should be started, including removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone.

A starting dose of 0.4-2 mg naloxone hydrochloride i.v. is recommended for adults. If needed, a similar dose can be given every 2 or 3 minutes, or be administered as continued infusion as 2 mg in 500 ml sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 50 mg/ml (5 %) solution. The infusion rate should be adjusted according to previous bolus injections and the individual response of the patient. If intravenous administration is impossible, naloxone hydrochloride can also be given intramuscularly or subcutaneously. Following intramuscular or subcutaneous administration the onset of action will be slower compared with intravenous administration. Intramuscular administration will give a more prolonged effect than intravenous administration. Respiratory depression due to overdose can persist longer than the effect of the opioid antagonist. Reversing the narcotic effect can give rise to acute pain and release of catecholamines. Intensive care unit treatment is important, if required by the patient's clinical condition. If severe or persistent hypotension occurs, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: opioids; Phenylpiperidine derivatives, ATC code: N02AB03

Fentanyl is an opioid analgesic which interacts predominantly with the μ-receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in opioid-naive patients fluctuate between 0.3–1.5 ng/ml; an increased incidence of adverse reactions is observed if serum levels exceed 2 ng/ml.

Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals.

The safety of transdermal fentanyl was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one patch with a release rate of 12.5 micrograms/h. Starting doses of 25 micrograms/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.

5.2 Pharmacokinetic Properties

Following administration of Osmanil, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.

Absorption

After the first application of Osmanil, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are dependant on the fentanyl transdermal patch size. For all practical purposes by the second 72-hour application, a steady state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.

Distribution

The plasma protein binding for fentanyl is 84 %.

Biotransformation

Fentanyl is metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.

Elimination

When treatment with Osmanil is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50 % in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration than is seen after an intravenous infusion.

Around 75 % of fentanyl is excreted into the urine, mostly as metabolites, with less than 10 % as unchanged active substance. About 9 % of the dose is recovered in the faeces, primarily as metabolites.

Pharmacokinetics in special groups

Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations.

Adjusting for body weight, clearance (l/h/kg) in paediatric patients, appears to be 82 % higher in children 2 to 5 years old and 25 % higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.

Long-term carcinogenicity studies have not been performed.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Adhesive layer

Polyacrylate adhesive layer

Backing film

Polypropylene foil

Blue printing ink

Release liner

Polyethylene terephthalate foil (siliconised)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 30 °C.

6.5 Nature And Contents Of Container

Each transdermal patch is packed in a separate sachet.

- Sachets made of composite foil containing the following layers from outside to inside:

coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn (thermoplastic ethylene-methacrylic acid copolymer).

Pack containing 3, 5, 10 or 20 transdermal patches

- Child resistant sachets made of composite foil containing the following layers from outside to inside:

PET foil, adhesive, aluminium foil, adhesive, Surlyn (ionomer-coex foil).

Pack containing 3, 5, 10 or 20 transdermal patches

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

High quantities of fentanyl remain in the transdermal patches even after use. Used transdermal patches should be folded with the adhesive surfaces inwards and discarded or whenever possible returned to the pharmacy. Any unused medicinal product should be discarded or returned to the pharmacy.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

8. Marketing Authorisation Number(S)

PL 17780/0315

9. Date Of First Authorisation/Renewal Of The Authorisation

29 May 2008

10. Date Of Revision Of The Text

14 April 2010

Legal category

POM/CD2

Antianginal agents

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Antianginal drugs are used to manage angina by either improving perfusion of the myocardium, reducing the metabolic demand of the heart, or both.

Two of the main groups of antianginal drugs are organic nitrates and calcium antagonists. They are vasodilators and improve myocardial perfusion, and reduced metabolic demand of the myocardium.

Beta-adrenoreceptor antagonists slow the heart rate therefore reduces metabolic demand of the heart.

See also

• nitrates

Medical conditions associated with antianginal agents:

• Anal Fissure and Fistula
• Angina
• Angina Pectoris Prophylaxis
• Cyanide Poisoning
• Esophageal Spasm
• Heart Attack
• Heart Failure
• High Blood Pressure
• Pulmonary Arterial Hypertension
• Raynaud's Syndrome

Drug List:

Nitro-Bid-Ointment

Nitroquick

Nitro-Dur-Patch

Ranexa

Imdur

Isordil

Nitrolingual-Pumpspray-Spray

Ismo

Nitrostat

Transderm-Nitro

Dilatrate-Sr

Isochron

Isoditrate

Isordil-Titradose

Minitran-Patch

Monoket

Nitrek-Transdermal

Nitro-Time-Controlled-Release-Capsules

Nitrocot

Nitrogard

Nitrol-Appli-Kit-Topical

Nitromist

Nitro-Td-Patch-A-Transdermal

Rectiv

Infibu

Infibu may be available in the countries listed below.

Ingredient matches for Infibu

Ibuprofen

Ibuprofen is reported as an ingredient of Infibu in the following countries:

• Colombia

International Drug Name Search

Flomax

Generic Name: tamsulosin hydrochloride

Dosage Form: capsule
FULL PRESCRIBING INFORMATION

1  INDICATIONS AND USAGE

Flomax® (tamsulosin hydrochloride) capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [see Clinical Studies (14)]. Flomax capsules are not indicated for the treatment of hypertension.

2  DOSAGE AND ADMINISTRATION

Flomax capsules 0.4 mg once daily is recommended as the dose for the treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour following the same meal each day.

For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of Flomax capsules can be increased to 0.8 mg once daily. Flomax capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2)].

If Flomax capsules administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily dose.

3  DOSAGE FORMS AND STRENGTHS

Capsule: 0.4 mg, olive green and orange hard gelatin, imprinted on one side with Flomax 0.4 mg and on the other side with BI 58

4  CONTRAINDICATIONS

Flomax capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of Flomax capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see Adverse Reactions (6.2)].

5  WARNINGS AND PRECAUTIONS

  Orthostasis

The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in Flomax capsule-treated patients than in placebo recipients. As with other alpha adrenergic blocking agents there is a potential risk of syncope [see Adverse Reactions (6.1)]. Patients beginning treatment with Flomax capsules should be cautioned to avoid situations in which injury could result should syncope occur [see Patient Counseling Information (17.1)].

  Drug Interactions

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. Flomax capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Flomax capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Flomax capsules should be used with caution in combination with cimetidine, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Flomax capsules should not be used in combination with other alpha adrenergic blocking agents [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Caution is advised when alpha adrenergic blocking agents including Flomax are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Caution should be exercised with concomitant administration of warfarin and Flomax capsules [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

  Priapism

Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition [see Patient Counseling Information (17.2)].

  Screening for Prostate Cancer

Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with Flomax capsules and at regular intervals afterwards [see Patient Counseling Information (17.3)].

  Intraoperative Floppy Iris Syndrome

 Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha1 blockers, including Flomax capsules [see Adverse Reactions (6.2)].

Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

 IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha1 blocker therapy prior to cataract surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract surgery is scheduled is not recommended.

  Sulfa Allergy

In patients with sulfa allergy, allergic reaction to Flomax capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering Flomax capsules.

6  ADVERSE REACTIONS

  Clinical Trials Experience

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

The incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg Flomax capsules were used. These studies evaluated safety in 1783 patients treated with Flomax capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either Flomax capsules 0.4 mg or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men.

Table 1   Treatment-Emergent1 Adverse Events Occurring in ≥2% of Flomax Capsules or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies

BODY SYSTEM/ ADVERSE EVENT	Flomax CAPSULES GROUPS		PLACEBO
	0.4 mg n=502	0.8 mg n=492	n=493
1 A treatment-emergent adverse event was defined as any event satisfying one of the following criteria: The adverse event occurred for the first time after initial dosing with double-blind study medication. The adverse event was present prior to or at the time of initial dosing with double-blind study medication and subsequently increased in severity during double-blind treatment; or The adverse event was present prior to or at the time of initial dosing with double-blind study medication, disappeared completely, and then reappeared during double-blind treatment.
2 Coding preferred terms also include cold, common cold, head cold, flu, and flu-like symptoms.
3 Coding preferred terms also include nasal congestion, stuffy nose, runny nose, sinus congestion, and hay fever.
BODY AS WHOLE
Headache	97 (19.3%)	104 (21.1%)	99 (20.1%)
Infection2	45 (9.0%)	53 (10.8%)	37 (7.5%)
Asthenia	39 (7.8%)	42 (8.5%)	27 (5.5%)
Back pain	35 (7.0%)	41 (8.3%)	27 (5.5%)
Chest pain	20 (4.0%)	20 (4.1%)	18 (3.7%)
NERVOUS SYSTEM
Dizziness	75 (14.9%)	84 (17.1%)	50 (10.1%)
Somnolence	15 (3.0%)	21 (4.3%)	8 (1.6%)
Insomnia	12 (2.4%)	7 (1.4%)	3 (0.6%)
Libido decreased	5 (1.0%)	10 (2.0%)	6 (1.2%)
RESPIRATORY SYSTEM
Rhinitis3	66 (13.1%)	88 (17.9%)	41 (8.3%)
Pharyngitis	29 (5.8%)	25 (5.1%)	23 (4.7%)
Cough increased	17 (3.4%)	22 (4.5%)	12 (2.4%)
Sinusitis	11 (2.2%)	18 (3.7%)	8 (1.6%)
DIGESTIVE SYSTEM
Diarrhea	31 (6.2%)	21 (4.3%)	22 (4.5%)
Nausea	13 (2.6%)	19 (3.9%)	16 (3.2%)
Tooth disorder	6 (1.2%)	10 (2.0%)	7 (1.4%)
UROGENITAL SYSTEM
Abnormal ejaculation	42 (8.4%)	89 (18.1%)	1 (0.2%)
SPECIAL SENSES
Blurred vision	1 (0.2%)	10 (2.0%)	2 (0.4%)

Signs and Symptoms of Orthostasis

In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group, and by 0.6% of patients (3 of 493) in the placebo group.

Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test.

Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received Flomax capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received Flomax capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1).

In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the Flomax capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the Flomax capsules 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group.

Because orthostasis was detected more frequently in Flomax capsule-treated patients than in placebo recipients, there is a potential risk of syncope [see Warnings and Precautions (5.1)].

Abnormal Ejaculation

Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with Flomax capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of Flomax capsules because of abnormal ejaculation was also dose-dependent, with 8 of 492 patients (1.6%) in the 0.8 mg group and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation.

Laboratory Tests

No laboratory test interactions with Flomax capsules are known. Treatment with Flomax capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA).

  Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Flomax capsules. Because these 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Flomax capsules.

Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, constipation, and vomiting have been received during the postmarketing period.

During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 blocker therapy [see Warnings and Precautions (5.5)].

7  DRUG INTERACTIONS

  Cytochrome P450 Inhibition

Strong and Moderate Inhibitors of CYP3A4 or CYP2D6

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.

Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of Flomax have not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when Flomax 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, Flomax 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of Flomax have not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with Flomax capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when Flomax 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Cimetidine

Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between Flomax capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between Flomax capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents including Flomax are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and Flomax capsules [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  Nifedipine, Atenolol, Enalapril

Dosage adjustments are not necessary when Flomax capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology (12.3)].

  Digoxin and Theophylline

Dosage adjustments are not necessary when a Flomax capsule is administered concomitantly with digoxin or theophylline [see Clinical Pharmacology (12.3)].

  Furosemide

Flomax capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the Flomax capsules dosage [see Clinical Pharmacology (12.3)].

8  USE IN SPECIFIC POPULATIONS

  Pregnancy

Teratogenic Effects, Pregnancy Category B.

Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. Flomax capsules are not indicated for use in women.

  Nursing Mothers

Flomax capsules are not indicated for use in women.

  Pediatric Use

Flomax capsules are not indicated for use in pediatric populations.

Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H2O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H2O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation.

  Geriatric Use

Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

  Renal Impairment

Patients with renal impairment do not require an adjustment in Flomax capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied [see Clinical Pharmacology (12.3)].

  Hepatic Impairment

Patients with moderate hepatic impairment do not require an adjustment in Flomax capsules dosage. Flomax has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

10  OVERDOSAGE

Should overdosage of Flomax capsules lead to hypotension [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)], support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.

11  DESCRIPTION

Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate.

Tamsulosin hydrochloride is (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether.

The empirical formula of tamsulosin hydrochloride is C20H28N2O5S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is:

Each Flomax capsule for oral administration contains tamsulosin hydrochloride 0.4 mg, and the following inactive ingredients: methacrylic acid copolymer dispersion, NF; microcrystalline cellulose, NF; triacetin, USP; calcium stearate, NF; talc, USP; FD&C blue No. 2; titanium dioxide; ferric oxide; gelatin, and trace amounts of black edible ink.

12  CLINICAL PHARMACOLOGY

  Mechanism of Action

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype.

Flomax capsules are not intended for use as an antihypertensive drug.

  Pharmacodynamics

Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH [see Use in Specific Populations (8.4) and Clinical Studies (14)].

  Pharmacokinetics

The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg.

Absorption

Absorption of tamsulosin hydrochloride from Flomax capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing.

Effect of Food

The time to maximum concentration (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when Flomax capsules are administered with food. Taking Flomax capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions (Figure 1).

Figure 1 Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single-Dose Administration of Flomax Capsules 0.4 mg Under Fasted and Fed Conditions (n=8)

The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a Flomax capsule is taken with a light breakfast or a high-fat breakfast (Table 2).

Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Flomax Capsules 0.4 mg Once Daily or 0.8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted

Pharmacokinetic Parameter	0.4 mg QD to healthy volunteers; n=23 (age range 18-32 years)		0.8 mg QD to healthy volunteers; n=22 (age range 55-75 years)
	Light Breakfast	Fasted	Light Breakfast	High-Fat Breakfast	Fasted
Cmin = observed minimum concentration
Cmax = observed maximum tamsulosin hydrochloride plasma concentration
Tmax = median time-to-maximum concentration
T1/2 = observed half-life
AUCτ = area under the tamsulosin hydrochloride plasma time curve over the dosing interval
Cmin (ng/mL)	4.0 ± 2.6	3.8 ± 2.5	12.3 ± 6.7	13.5 ± 7.6	13.3 ± 13.3
Cmax (ng/mL)	10.1 ± 4.8	17.1 ± 17.1	29.8 ± 10.3	29.1 ± 11.0	41.6 ± 15.6
Cmax/Cmin Ratio	3.1 ± 1.0	5.3 ± 2.2	2.7 ± 0.7	2.5 ± 0.8	3.6 ± 1.1
Tmax (hours)	6.0	4.0	7.0	6.6	5.0
T1/2 (hours)	-	-	-	-	14.9 ± 3.9
AUCτ  (ng•hr/mL)	151 ± 81.5	199 ± 94.1	440 ± 195	449 ± 217	557 ± 257

Distribution

The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.

Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs.

Metabolism

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal.

Excretion

On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with Flomax capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h).

Specific Populations

Pediatric Use

Flomax capsules are not indicated for use in pediatric populations [see Use in Specific Populations (8.4)].

Geriatric (Age) Use

Cross-study comparison of Flomax capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years [see Use in Specific Populations (8.5)].

Renal Impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30≤ CLcr <70 mL/min/1.73 m2) or moderate-severe (10≤ CLcr <30 mL/min/1.73 m2) renal impairment and 6 normal subjects (CLcr >90 mL/min/1.73 m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in Flomax capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied [see Use in Specific Populations (8.6)].

Hepatic Impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in Flomax capsules dosage. Flomax has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interactions

Cytochrome P450 Inhibition

Strong and Moderate Inhibitors of CYP3A4 or CYP2D6

The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for 5 days on the pharmacokinetics of a single Flomax capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of Flomax have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single Flomax capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when Flomax 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, Flomax 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of Flomax have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with Flomax capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when Flomax 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Cimetidine

The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the pharmacokinetics of a single Flomax capsule 0.4 mg dose was investigated in 10 healthy volunteers (age range 21 to 38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between Flomax capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between Flomax capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents, including Flomax, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and Flomax capsules [see Warnings and Precautions (5.2) and Drug Interactions (7.4)].

Nifedipine, Atenolol, Enalapril

In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, atenolol, or enalapril for at least 3 months, Flomax capsules 0.4 mg for 7 days followed by Flomax capsules 0.8 mg for another 7 days (n=8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when Flomax capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Drug Interactions (7.5)].

Digoxin and Theophylline

In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving Flomax capsules 0.4 mg/day for 2 days, followed by Flomax capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a Flomax capsule is administered concomitantly with digoxin or theophylline [see Drug Interactions (7.6)].

Furosemide

The pharmacokinetic and pharmacodynamic interaction between Flomax capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range 21 to 40 years). Flomax capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the Flomax capsules dosage [see Drug Interactions (7.7)].

13  NONCLINICAL TOXICOLOGY

  Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.

Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.

The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if Flomax capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.

Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.

Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.

Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

14  CLINICAL STUDIES

Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received Flomax capsules 0.4 mg once daily, 491 received Flomax capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe.

In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, Flomax capsules 0.4 mg once daily, or Flomax capsules 0.8 mg once daily. Patients in Flomax capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction.

Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with Flomax capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the Flomax capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the Flomax capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between