Aknemin 100

1. Name Of The Medicinal Product

Aknemin

2. Qualitative And Quantitative Composition

Minocycline base 100 mg (as the hydrochloride Ph Eur) per capsule.

3. Pharmaceutical Form

Capsule.

4. Clinical Particulars

4.1 Therapeutic Indications

Minocycline is an antibiotic with a spectrum of activity similar to other tetracyclines but more active against Staphylococcus aureus and Nocardia spp.

It is indicated for the treatment of organisms sensitive to tetracyclines such as acne, respiratory infections, gonorrhoea, nocardiosis, staphylococcal infections; the chemoprophylaxis of meningococcal infections.

4.2 Posology And Method Of Administration

For oral administration.

Adults:

1) Routine antibiotic use: 200 mg daily in divided doses.

2) Acne: 50 mg twice daily or 100 mg once daily.

3) Gonorrhoea: In adult males, 200 mg initially followed by 100 mg every 12 hours for a minimum of 4 days with post-therapy cultures within 2-3 days. Adult females may require more prolonged therapy.

4) Prophylaxis of meningococcal infections: 100 mg twice daily for five days, usually followed by a course of rifampicin.

Children:

Aknemin is not recommended for children under 12 years old. For children above 12 years old the recommended dose is 50 mg every 12 hours or 100 mg once daily.

The Elderly:

Aknemin may be used at the normal recommended dosage in elderly patients but caution is advised in patients with renal impairment.

Unlike earlier tetracyclines, absorption of Aknemin is not impaired significantly by the intake of food or moderate amounts of milk.

The treatment of acne should be continued for a minimum of 6 weeks. If after 6 months there is no satisfactory response, Aknemin should be discontinued and other therapies considered. If Aknemin is to be continued for more than 6 months, patients should be monitored at least 3 monthly thereafter for signs and symptoms of hepatitis or SLE (See 4.4).

4.3 Contraindications

Hypersensitivity to tetracyclines, systemic lupus erythematosus, renal failure, children under 12 years old, pregnancy, lactation.

4.4 Special Warnings And Precautions For Use

Aknemin should be used with caution in patients with hepatic dysfunction and in conjunction with alcohol and other hepatotoxic drugs.

Cross-resistance between tetracyclines may develop in micro-organisms and cross-sensitisation in patients. Aknemin should be discontinued if there are signs or symptoms of overgrowth of resistant organisms, eg enteritis, glossitis, stomatitis, vaginitis, pruritus ani or staphylococcal enteritis.

Patients taking oral contraceptives should be warned that if diarrhoea or breakthrough bleeding occurs there is a possibility of contraceptive failure.

Rare cases of autoimmune hepatotoxicity and isolated cases of systemic lupus erythematosus (SLE) and also exacerbations of pre-existing SLE have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, or suffer exacerbation of existing SLE, minocycline should be discontinued.

Caution should be exercised in patients with Myasthenia Gravis as tetracyclines can cause weak neuromuscular blockade.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tetracyclines decrease plasma prothrombin activity; reduced doses of concomitant anticoagulants may therefore be required. Aknemin should not be used with penicillins. The absorption of Aknemin is impaired by concomitant administration of antacids and preparations containing iron, calcium, aluminium, magnesium, bismuth or zinc salts. Diuretics may aggravate nephrotoxicity by volume depletion.

4.6 Pregnancy And Lactation

Aknemin should not be used in pregnancy unless essential. Animal studies have indicated that tetracyclines cross the placenta, are found in foetal tissues, and can cause toxicity in the foetus usually related to a retardation of skeletal development. Yellow-brown discolouration of the teeth and enamel hypoplasia can occur when drugs of the tetracycline group are administered after the first trimester of pregnancy.

Aknemin should not be given to lactating women.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned of the hazards of driving or operating machinery until the effect of treatment is known (See 4.8).

4.8 Undesirable Effects

Blood and lymphatic system disorders: Haemolytic anaemia, thrombocytopenia, neutropenia and eosinophilia have been reported with tetracyclines.

Hypersensitivity reactions: Urticaria, fever, arthralgia, angioneurotic oedema, anaphylaxis and anaphylactoid purpura.

Nervous system disorders: Hyperaesthesia, paraesthesia have rarely been reported.

Headache, dizziness, vertigo and ataxia may occur. These disturbances are reversible within 3-48 hours of discontinuing therapy and occur less frequently when a low dose is given.

As with other tetracyclines, bulging fontanelles in infants and benign intracranial hypertension in adults have been reported. Treatment should be stopped if evidence of raised intracranial pressure develops.

Eye disorders: There are isolated cases of discolouration of the conjunctiva and lacrimal secretions. (See 4.6).

Ear and labyrinth disorders: Impaired hearing has rarely been reported. Tinnitus may occur.

Cardiac disorders: Rarely pericarditis has been reported.

Respiratory, thoracic and mediastinal disorders: Rarely pulmonary infiltration has been reported.

Gastrointestinal disorders: Disturbances like anorexia, nausea, vomiting, diarrhoea, dyspepsia, dysphagia, antibiotic-associated colitis may occur. There have been isolated incidences of pancreatitis. A few cases of oesophagitis and oesophageal ulceration have been reported. To reduce the risk of oesophageal irritation and ulceration the capsules should be administered with adequate amount of fluids and probably not be given at bedtime or to patients with oesophageal obstruction or compression

Hepato-biliary disorders: In common with other tetracyclines transient increases in liver function test values and, rarely, hepatitis have been reported. Some hepatic reactions have an autoimmune basis, and may occur after several months of minocycline treatment (See 4.2).

Skin and subcutaneous tissue disorders: Dermatological reactions are rare but erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity and alopecia have been reported.

Hyperpigmentation of skin have been reported occasionally.

Renal and urinary disorders: Rarely acute renal failure has been reported.

Other: When given over long periods, tetracyclines have been reported to produce brownish-black microscopic discolouration of thyroid tissue; no abnormalities of function are known to occur.

Discolouration of teeth and buccal mucosa have been reported occasionally. These are generally reversible on cessation of therapy. There are isolated cases of breast secretions and perspiration. (See 4.6).

4.9 Overdose

There is no specific antidote. Treatment is gastric lavage with appropriate supportive treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Minocycline is an antibiotic with a spectrum of activity similar to other tetracyclines but is more active against Staphylococcus aureus and Nocardia spp.

5.2 Pharmacokinetic Properties

Minocycline is almost completely absorbed after oral administration.

Absorption is not significantly affected by the presence of food or milk. Doses of 200 mg followed by 100 mg every 12 hours produce plasma concentrations of 1 to 4 mg per ml.

Plasma half life is 12-16 hours in patients with normal renal function but increased in renal impairment.

Minocycline is widely distributed in body fluids and tissue. It crosses the placenta and is excreted in breast milk.

5.3 Preclinical Safety Data

No relevant preclinical safety data have been generated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyethylene glycol

Erythrosine (E127)

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Gelatin

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25°C

6.5 Nature And Contents Of Container

Aluminium/PVC strip of 14 in a cardboard outer carton containing 28 or 56 capsules.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Almirall Hermal GmbH,

Scholtzstrasse 3,

D-21465,

Reinbek,

Germany.

8. Marketing Authorisation Number(S)

PL 33016/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

30^th January 2009

10. Date Of Revision Of The Text

5^th August 2010

Naropin 2 mg / ml solution for infusion

1. Name Of The Medicinal Product

Naropin^® 2 mg/ml solution for infusion

2. Qualitative And Quantitative Composition

Naropin^® 2 mg/ml:

1 ml solution for infusion contains ropivacaine hydrochloride monohydrate equivalent to 2 mg ropivacaine hydrochloride.

1 bag of 100 or 200 ml solution for infusion contains ropivacaine hydrochloride monohydrate equivalent to 200 mg and 400 mg ropivacaine hydrochloride respectively.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for infusion for perineural and epidural administration (100 and 200 ml).

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Naropin is indicated for:

1. Surgical anaesthesia

2. Acute pain management

Continuous peripheral nerve block via a continuous infusion or intermittent bolus injections, e.g. postoperative pain management

3. Acute pain management in paediatrics:

(per- and postoperative)

- Caudal epidural block in neonates, infants and children up to and including 12 years.

- Continuous epidural infusion in neonates, infants and children up to and including 12 years.

4.2 Posology And Method Of Administration

Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Posology

Adults and children above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

	Conc.	Volume	Dose	Onset	Duration
	mg/ml	ml	mg	minutes	hours
Surgical anaesthesia
Lumbar Epidural Administration
Surgery	7.5	15–25	113–188	10–20	3–5
	10	15–20	150–200	10–20	4–6
Caesarean section	7.5	15–20	113–150(1)	10–20	3–5
Thoracic Epidural Administration
To establish block for postoperative pain relief	7.5	5–15 (depending on the level of injection)	38–113	10–20	n/a(2)
Major Nerve Block *
Brachial plexus block	7.5	30–40	225–300(3)	10–25	6–10
Field Block	7.5	1–30	7.5–225	1–15	2–6
(e.g. minor nerve blocks and infiltration)
Acute pain management
Lumbar Epidural Administration
Bolus	2	10–20	20–40	10–15	0.5–1.5
Intermittent injections (top up) (e.g. labour pain management)	2	10–15 (minimum interval 30 minutes)	20–30
Continuous infusion e.g. labour pain	2	6–10 ml/h	12–20 mg/h	n/a(2)	n/a(2)
Postoperative pain management	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Thoracic Epidural Administration
Continuous infusion (postoperative pain management)	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Field Block
(e.g. minor nerve blocks and infiltration)	2	1–100	2–200	1–5	2–6
Peripheral nerve block (Femoral or interscalene block)
Continuous infusion or intermittent injections (e.g. postoperative pain management)	2	5–10 ml/h	10–20 mg/h	n/a	n/a
The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column 'Dose' reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.
* With regard to major nerve block, only for brachial plexus block a dose recommendation can be given. For other major nerve blocks lower doses may be required. However, there is presently no experience of specific dose recommendations for other blocks.
(1) Incremental dosing should be applied, the starting dose of about 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) to be given over 3–5 minutes. Two extra doses, in total an additional 50mg, may be administered as needed. (2) n/a = not applicable (3) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, (see section 4.4. Special warnings and special precautions for use).

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The Naropin 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Method of administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) (Xylocaine^® 2% with Adrenaline (epinephrine) 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.

For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6–14 ml (12–28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it. With this technique a significant reduction in the need for opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 μg/ml has been given for postoperative pain management for up to 72 hours. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects. The combination of Naropin and fentanyl has been investigated only for Naropin 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg Naropin 7.5 mg/ml and interscalene block with 225 mg Naropin 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with Naropin 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Concentrations above 7.5 mg/ml Naropin have not been documented for Caesarean section.

Paediatric patients 0 up to and including 12 years of age:

	Conc.	Volume	Dose
	mg/ml	ml/kg	mg/kg
ACUTE PAIN MANAGEMENT
(per and postoperative)
Single Caudal Epidural Block Blocks below T12, in children with a body weight up to 25 kg	2.0	1	2
Continuous Epidural Infusion In children with a body weight up to 25 kg
0 up to 6 months Bolus dosea Infusion up to 72 hours	2.0 2.0	0.5–1 0.1 mL/kg/h	1–2 0.2 mg/kg/h
6 up to 12 months Bolus dosea Infusion up to 72 hours	2.0 2.0	0.5–1 0.2 mL/kg/h	1–2 0.4 mg/kg/h
1 to 12 years Bolus doseb Infusion up to 72 hours	2.0 2.0	1 0.2 mL/kg/h	2 0.4 mg/kg/h
The dose in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight, a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. The volume for single caudal epidural block and the volume for epidural bolus doses should not exceed 25 mL in any patient. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. a Doses in the low end of the dose interval are recommended for thoracic epidural blocks while doses in the high end are recommended for lumbar or caudal epidural blocks. b Recommended for lumbar epidural blocks. It is good practice to reduce the bolus dose for thoracic epidural analgesia.

Method of Administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. The patient's vital functions should be observed closely during the injection. If toxic symptoms occur, the injection should be stopped immediately.

A single caudal epidural injection of ropivacaine 2 mg/ml produces adequate postoperative analgesia below T12 in the majority of patients when a dose of 2 mg/kg is used in a volume of 1 ml/kg. The volume of the caudal epidural injection may be adjusted to achieve a different distribution of sensory block, as recommended in standard textbooks. In children above 4 years of age, doses up to 3 mg/kg of a concentration of ropivacaine 3 mg/ml have been studied. However, this concentration is associated with a higher incidence of motor block.

Fractionation of the calculated local anaesthetic dose is recommended, whatever the route of administration.

The use of ropivacaine in premature children has not been documented.

4.3 Contraindications

Hypersensitivity to ropivacaine or to other local anaesthetics of the amide type.

General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special Warnings And Precautions For Use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see section 4.8 Undesirable effects and 4.9 Overdose) such as inadvertent subarachnoid injection, which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

Patients treated with anti-arrhythmic drugs class III (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Head and neck blocks

Certain local anaesthetic procedures, such as injections in the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used.

Major peripheral nerve blocks

Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.

Hypersensitivity

A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used.

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination. Normally there is no need to modify the dose in patients with impaired renal function when used for single dose or short-term treatment. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Acute porphyria

Naropin^® solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients, according to standard textbooks and/or in consultation with disease area experts.

Excipients with recognised action/effect

This medicinal product contains maximum 3.7 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Prolonged administration

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin, see section 4.5.

Paediatric patients

Neonates may need special attention due to immaturity of metabolic pathways. The larger variations in plasma concentrations of ropivacaine observed in clinical trials in neonates suggest that there may be an increased risk of systemic toxicity in this age group, especially during continuous epidural infusion. The recommended doses in neonates are based on limited clinical data. When ropivacaine is used in this patient group, regular monitoring of systemic toxicity (e.g. by signs of CNS toxicity, ECG, SpO₂) and local neurotoxicity (e.g. prolonged recovery) is required, which should be continued after ending infusion, due to a slow elimination in neonates.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Naropin with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4 Special warnings and precautions for use).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co

In vivo, the plasma clearance of ropivacaine was reduced by 15% during co

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Pregnancy And Lactation

Pregnancy

Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fœtal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Lactation

There are no data available concerning the excretion of ropivacaine into human milk.

4.7 Effects On Ability To Drive And Use Machines

No data are available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

General

The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.

Table of adverse drug reactions

Within each system organ class, the ADRs have been ranked under the headings of frequency, most frequent reactions first.

Very common (>1/10)	Vascular Disorders	Hypotensiona
	Gastrointestinal Disorders	Nausea
Common (>1/100)	Nervous System Disorders	Headache, paraesthesia, dizziness
	Cardiac Disorders	Bradycardia, tachycardia
	Vascular Disorders	Hypertension
	Gastrointestinal Disorders	Vomitingb
	Renal and Urinary Disorders	Urinary retention
	General Disorder and Administration Site Conditions	Temperature elevation, rigor, back pain
Uncommon (>1/1,000)	Psychiatric Disorders	Anxiety
	Nervous System Disorders	Symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, muscular twitching, tremor)* , Hypoaesthesia.
	Vascular Disorders	Syncope
	Respiratory, Thoracic and Mediastinal Disorders	Dyspnoea
	General Disorders and Administration Site Conditions	Hypothermia
Rare (>1/10,000)	Cardiac Disorders	Cardiac arrest, cardiac arrhythmias
	General Disorder and Administration Site Conditions	Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)

^a Hypotension is less frequent in children (>1/100).

^b Vomiting is more frequent in children (>1/10).

^* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

Class-related adverse drug reactions:

Neurological complications

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.

Total spinal block

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). Such reactions are caused by high blood concentration of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularized areas, see also section 4.4. CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.

Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. See also section 4.4.

Treatment of acute systemic toxicity

See section 4.9 Overdose.

4.9 Overdose

Symptoms:

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak plasma concentrations may not be reached for one to two hours, depending on the site of the inj

Istodax

Generic Name: romidepsin (Intravenous route)

roe-mi-DEP-sin

Commonly used brand name(s)

In the U.S.

• Istodax

Available Dosage Forms:

• Powder for Solution

Pharmacologic Class: Histone Deacetylase Inhibitor

Uses For Istodax

Romidepsin injection is used to treat certain types of cancer of the white blood cells called cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). This medicine is used in patients with CTCL and PTCL who have already been treated with other medicines.

Romidepsin interferes with the growth of cancer cells, which are eventually destroyed by the body. Since the growth of normal body cells may also be affected by romidepsin, other unwanted effects will also occur. Some of these may be serious and must be reported to your doctor. Some unwanted effects may not be serious but may cause concern. Some of the unwanted effects do not occur until months or years after the medicine is used.

Before you begin treatment with romidepsin, you and your doctor should talk about the benefits this medicine will do as well as the risks of using it.

This medicine is to be given only by or under the direct supervision of a doctor.

Before Using Istodax

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

Allergies

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

Pediatric

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

Geriatric

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

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

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

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir


• Carbamazepine


• Clarithromycin


• Dexamethasone


• Indinavir


• Itraconazole


• Ketoconazole


• Nefazodone


• Nelfinavir


• Phenobarbital


• Phenytoin


• Rifabutin


• Rifampin


• Rifapentine


• Ritonavir


• Saquinavir


• St John's Wort


• Telithromycin


• Voriconazole

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Blood or bone marrow problems (e.g., anemia, leukopenia, thrombocytopenia) or


• Heart or blood vessel disease or


• Heart rhythm problems (e.g., congenital long QT syndrome), or history of or


• Mineral imbalance (e.g., magnesium, potassium imbalance)—Use with caution. May make these conditions worse.

• Infection—May decrease your body's ability to fight infection.

• Kidney disease, severe or


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

Proper Use of Istodax

You will receive this medicine while you are in a hospital or cancer treatment center.

This medicine is given through a needle placed in one of your veins. It is usually given on Day 1, Day 8, and Day 15 of a 28-day cycle treatment. This 3-day treatment is given again every 28 days until your body responds to the medicine. Each treatment usually takes about 4 hours.

This medicine comes with a patient information leaflet. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Precautions While Using Istodax

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Blood tests may be needed to check for unwanted effects.

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

Romidepsin can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

You may get infections (including pneumonia and sepsis) more easily while using this medicine. These can occur during treatment and within 30 days after treatment. Tell your doctor right away if you have a fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems.

This medicine can cause changes in heart rhythms, such as a condition called QT prolongation. It may change the way your heart beats and cause fainting or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or uneven heartbeats; chest pain; or shortness of breath.

This medicine may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount; joint pain, stiffness, or swelling; lower back, side, or stomach pain; a rapid weight gain; swelling of the feet or lower legs; or unusual tiredness or weakness.

Cancer medicines can cause nausea and/or vomiting in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these side effects.

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

Istodax Side Effects

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

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

More common

• Abdominal or stomach cramps or pain


• black, tarry stools


• bleeding gums


• blood in the urine or stools


• blurred vision


• bone pain


• chest pain


• chills


• coma


• confusion


• convulsions


• cough or hoarseness


• decreased urine output


• difficulty with breathing


• dizziness


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


• drowsiness


• dry mouth


• fast or irregular heartbeat


• fever


• flushed, dry skin


• fruit-like breath odor


• headache


• increased hunger


• increased thirst


• increased urination


• joint pain, stiffness, or swelling


• loss of appetite


• lower back or side pain


• mood or mental changes


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


• muscle pain


• muscle spasms (tetany) or twitching seizures


• nausea or vomiting


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


• painful or difficult urination


• pale skin


• pinpoint red spots on the skin


• shortness of breath


• sore throat


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


• sweating


• swelling of the face, ankles, feet, lower legs, or hands


• swollen glands


• trembling


• tremor


• troubled breathing


• troubled breathing with exertion


• unexplained weight loss


• unusual bleeding or bruising


• unusual tiredness or weakness

Less common

• Fainting


• fast, pounding, or irregular heartbeat or pulse


• swelling

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

More common

• Change in taste


• constipation


• cracks in the skin


• diarrhea


• itching skin


• lack or loss of strength


• loss of appetite


• loss of heat from the body


• loss of taste


• red, swollen skin


• scaly skin


• weight loss

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

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

See also: Istodax side effects (in more detail)

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

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.

More Istodax resources

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

• Istodax Prescribing Information (FDA)


• Istodax Consumer Overview


• Istodax Monograph (AHFS DI)


• Istodax MedFacts Consumer Leaflet (Wolters Kluwer)


• Romidepsin Professional Patient Advice (Wolters Kluwer)

Compare Istodax with other medications

• Cutaneous T-cell Lymphoma
• Peripheral T-cell Lymphoma

ACWY Vax Vaccine

1. Name Of The Medicinal Product

ACWY Vax - powder and solvent for solution for injection in a pre-filled syringe

Meningococcal polysaccharide groups A, C, Y and W₁₃₅ vaccine

2. Qualitative And Quantitative Composition

After reconstitution, 1 dose (0.5 ml) contains:
Neisseria meningitidis group A polysaccharide	50 µg
Neisseria meningitidis group C polysaccharide	50 µg
Neisseria meningitidis group Y polysaccharide	50 µg
Neisseria meningitidis group W135 polysaccharide	50 µg
For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection in a pre-filled syringe.

The powder is white. The solvent is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

Active immunisation of children older than 2 years, adolescents and adults against invasive meningococcal disease caused by meningococci of groups A, C, W₁₃₅ and Y.

ACWY Vax should be used in accordance with available official recommendations.

4.2 Posology And Method Of Administration

Posology

One dose of 0.5 ml.

Subjects who remain at increased risk of invasive meningococcal disease may be revaccinated at intervals (see persistence of immune response in Section 5.1). Intervals should be in accordance with available official recommendations.

Method of administration

ACWY Vax is for deep subcutaneous injection only.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Hypersensitivity after previous administration of ACWY Vax.

As with other vaccines, the administration of ACWY Vax should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection, such as a cold, is not a contra-indication for immunisation.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of anaphylactic reactions following the administration of the vaccine.

Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.

ACWY Vax should under no circumstances be administered intravascularly or intradermally.

ACWY Vax will only confer protection against Neisseria meningitidis groups A, C, W₁₃₅ and Y. Protection cannot be guaranteed in every individual vaccinated.

The vaccine may not elicit a protective immune response in subjects with impaired immune systems.

Group C, W₁₃₅ and Y polysaccharides are poorly immunogenic in children less than 24 months of age. Group A polysaccharide induces an antibody response in children from the age of 6 months. However, the response is lower than that observed in older subjects and may be transient.

Group C polysaccharide may induce immunological hyporesponsiveness to further doses of polysaccharide C or to meningococcal group C conjugate vaccine. The clinical relevance of this phenomenon remains unknown.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no data on concomitant administration of ACWY Vax and other vaccines.

Different injection sites should be used when concomitant administration with other injectable vaccines can not be avoided.

4.6 Pregnancy And Lactation

Pregnancy

Adequate human data on use during pregnancy and adequate animal reproduction studies are not available.

Nevertheless, vaccination during pregnancy may be considered when there is an increased risk for meningococcal disease.

Lactation

Adequate data on the administration of ACWY Vax to women who are breast-feeding are not available.

However, ACWY Vax may be administered to breast-feeding women when there is an increased risk of meningococcal disease.

4.7 Effects On Ability To Drive And Use Machines

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

4.8 Undesirable Effects

In recent clinical studies, ACWY Vax was administered to 502 subjects.

The most commonly reported adverse reactions were pain at the injection site and redness at the injection site.

Adverse reactions occurring during these studies were mostly reported within 48 hours following vaccination.

Adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency as follows.

Frequencies are reported as:

Very common: (

Common: (

Uncommon: (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders:

Very Common: headache

Common: drowsiness

Uncommon: dizziness

Gastrointestinal disorders:

Common: gastrointestinal symptoms e.g. nausea, vomiting and diarrhoea

Skin and subcutaneous tissue disorders:

Uncommon: urticaria, rash

Metabolism and nutrition disorders:

Common: loss of appetite

General disorders and administration site conditions:

Very common: pain, redness at the injection site, fatigue

Common: fever, swelling at the injection site

Psychiatric disorders:

Common: irritability

In a WHO study conducted in Ghana, ACWY Vax was administered to 177 adults. The following adverse reactions were observed in this trial:

Very common: tenderness at injection site

Common: induration at injection site.

In addition, the following adverse reactions have been reported during post-marketing surveillance:

Skin and subcutaneous tissue disorders:

Angioneurotic oedema

Musculoskeletal and connective tissue disorders:

Arthralgia, musculoskeletal stiffness

General disorders and administration site conditions:

Influenza-like symptoms, chills

Immune system disorders:

Allergic reactions, including anaphylactic and anaphylactoid reactions

4.9 Overdose

Cases of overdose (up to 10 times the recommended dose) have been reported during post-marketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Bacterial vaccines, ATC code: J07AH04

Immunogenicity data

ACWY Vax induces bactericidal antibodies against meningococci of groups A, C, W₁₃₅ and Y.

The current formulation of ACWY Vax was shown immunologically non-inferior to the previous formulation of the vaccine in a trial conducted in Lebanon in 161 subjects aged 2-30 years.

The immunogenicity of the previous formulation of ACWY Vax was evaluated in four clinical studies conducted in Belgium, Lebanon, Poland and Taiwan (N =341) in subjects aged 2-30 years.

Antibody titres were measured with the serum bactericidal assay (SBA).

Vaccine response was defined as seroconversion for initially seronegative subjects (with SBA titre below 1:8) or as four-fold increase in SBA titre from pre to post vaccination for initially seropositive subjects.

The percentage of vaccine responders observed in the four clinical studies conducted with the previous formulation were as follows:

In children aged 2-5 years: Group A - 69.1%, Group C - 93.1%, Group W₁₃₅ - 89.3%, Group Y - 79.2%.

In subjects aged 6-30 years: Group A - 72.2%, Group C - 95.4%, Group W₁₃₅ - 92.3%, Group Y -81.2%.

In initially seronegative subjects seroconversion rates were 100% for Group A and Y, and at least 92.9% for Group C and W_135.

The risk of meningococcal disease is much higher in individuals with late complement component deficiency (LCCD) because of their inability to kill meningococci via the classical and alternative pathways. However, ACWY Vax induces anti-capsular polysaccharide antibodies against each of the four groups in LCCD subjects. In spite of the complement deficiency, killing of meningococci A, C, W₁₃₅ and Y is observed when sera from LCCD subjects vaccinated with ACWY Vax are incubated with human neutrophils.

Efficacy data

In response to a meningococcal disease epidemic in Burkina Faso, a mass vaccination campaign with Mencevax ACW was performed in more than 1.68 million children and adults aged from 2 to 29 years. The vaccine effectiveness against group A and W₁₃₅ disease was 95.8% (95% CI: 81.8%-99.0%) for persons with reported vaccination.

Persistence of immune response

Literature data supports the persistence of vaccine induced antibody response for at least 3 years.

An ongoing clinical study has demonstrated that 100% of subjects aged 18-25 years had bactericidal antibody titres ₁₃₅ and Y and 96% for group C two years after vaccination.

In a study conducted in Ghana in 177 subjects aged 15-34 years, 100%, 88.4% and 93.5% of subjects had SBA titres ₁₃₅, respectively at approximately one year after vaccination with ACWY Vax.

In studies conducted among complement-deficient subjects, the antibodies persisted for 3 years post vaccination with ACWY Vax and the revaccination restored antibody concentrations.

5.2 Pharmacokinetic Properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on general safety tests performed in animals.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder :

Sucrose

Trometamol

Solvent:

Sodium chloride

Water for injections

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

After reconstitution, the vaccine should be used immediately. However, chemical and physical in-use stability has been demonstrated for 8 hours at 2-8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Powder in a vial (type I glass) with a stopper and solvent (0.5 ml) in a pre-filled syringe (type I glass) with a stopper with or without needles– pack size of 1.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The vaccine should be inspected visually for any foreign particulate matter and/or other coloration prior to administration. In the event of either being observed, discard the vaccine.

ACWY Vax must be reconstituted by adding the entire content of the supplied container of solvent to the vial containing the powder. The powder should be completely dissolved in the solvent.

The reconstituted vaccine is a clear colourless solution.

7. Marketing Authorisation Holder

SmithKline Beecham plc

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 10592/0301

9. Date Of First Authorisation/Renewal Of The Authorisation

23/06/2008

10. Date Of Revision Of The Text

09/02/2011

POM