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Baclofen 10 mg / 5 ml Solution for Infusion

1. Name Of The Medicinal Product

Baclofen 10 mg/5 ml solution for infusion

2. Qualitative And Quantitative Composition

Baclofen 10 mg/5 ml solution for infusion:

1 ml solution for infusion contains 2.0 mg baclofen.

1 ampoule with 5 ml solution for infusion contains 10 mg baclofen.

1 ampoule with 5 ml solution for infusion contains 17.7 mg sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Baclofen 10 mg/5 ml solution for infusion:

Solution for infusion

Clear, colourless solution for infusion with pH 5.0-7.0 and osmolarity260-320 mOsm/L.

4. Clinical Particulars

4.1 Therapeutic Indications

Baclofen 10 mg/20 ml and Baclofen 10 mg/5 ml solution for infusion:

For the treatment of severe chronic spasticity associated with multiple sclerosis, with injuries to the spinal cord or of cerebral origin that cannot be treated successfully with a standard treatment.

Paediatric population

Baclofen is indicated in patients aged 4 to <18 years with severe chronic spasticity of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) who are unresponsive to orally administered antispastics (including oral baclofen) and/or who experience unacceptable side effects at effective oral doses.

4.2 Posology And Method Of Administration

Baclofen is intended for administration in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable pumps suitable for continuous administration of intrathecal baclofen into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to. This procedure is necessary because of the large differences between the therapeutically effective dosages required by different patients. Long-term administration is achieved by means of an implantable pump for continuous delivery of baclofen solution to the cerebrospinal fluid using Baclofen 10mg/20ml or Baclofen 10mg/5ml.

The efficacy of Baclofen has been demonstrated in clinical studies using the SyncroMed infusion system. This system is a delivery system with a refillable reservoir that is implanted subcutaneously, usually in the abdominal wall. The instrument is connected to an intrathecal catheter that also runs subcutaneously into the subarachnoid space. There is as yet no confirmed experience with other implantable pump systems.

Before Baclofen is administered, the subarachnoid space of patients with post-traumatic spasticity should be investigated by myelography. If radiological signs of arachnoiditis are found, treatment with Baclofen should not be instituted.

Before administration of Baclofen, the solution should be checked for clarity and colourlessness. Only clear solutions practically free from particles should be used. If clouding or discoloration is evident, then the solution should not be used and should be discarded.

The solution it contains is stable, isotonic, pyrogen and antioxidant free and has a pH-value of 5.5–7.0.

Every ampoule is intended for single use only.

Baclofen 10 mg/20 ml solution for infusion:

Baclofen 10 mg/5 ml solution for infusion:

Implantation phase/dosage-titration phase (under inpatient conditions)

After the action of baclofen has been confirmed in the test phase, intrathecal infusion is started using one of the implantable infusion pumps given above. The antispastic action of baclofen sets in 6 to 8hours after the start of continuous infusion and reaches its maximum within 24 to 48hours.

The initial total daily dosage of Baclofen is calculated as follows:

If the duration of action of the test dose is more than 12hours, this is taken as the initial daily dose. If the duration of action of the test dose is shorter than 12hours, then the initial daily dose is double the test dose. The dosage should not be increased within the first 24hours.

After the first day of treatment, the dosage can slowly be titrated from day to day in order to achieve the desired action. The increase in the dosage per day should not exceed 10 to 30% of the previous dose in patients with spinal spasticity and 5 to 15% in patients with cerebral spasticity. When using a programmable pump, it is advisable to adjust the dosage only once in any 24-hour period. With non-programmable pumps with a 76cm catheter length that release 1ml of solution per day, intervals of 48hours are recommended in order to be able to assess the reaction to the dosage. If a considerable rise in the daily dosage does not increase the clinical action, then the function of the pump and the patency of the catheter should be checked.

In general, the dosage is increased to a maintenance dosage of 300 to 800microgram/day in patients with spinal spasticity. Patients with cerebral spasticity usually require lower doses (see below).

Long-term treatment phase

The aim is to use the lowest dosage with which the spasticity can be well controlled without the appearance of unacceptable adverse reactions. As over the course of the treatment the therapeutic effect can diminish or the severity of the spasticity can alter, dosage titration under in-patient conditions is usually necessary in the long-term treatment phase. Here also, the daily dosage can be increased by 10 to 30% in patients with spinal spasticity and 5 to 20% (upper limit) in patients with cerebral spasticity by altering the delivery rate of the pump or by changing the concentration of baclofen in the reservoir. Conversely, if adverse reactions occur, the daily dosage can be reduced by 10 to 20%.

If the dosage must suddenly be increased in order to achieve a sufficient effect, the possibility of a pump malfunction or a kink, rupture (tear) or displacement of the catheter must be considered.

The maintenance dosage for the long-term treatment of patients with spinal spasticity using continuous intrathecal infusion of Baclofen is normally 300 to 800microgram of baclofen per day. The lowest and highest daily dosages recorded as administered to individual patients during dosage titration are 12microgram and 2003microgram respectively (US studies). Experience with dosages above 1000microgram/day is limited. During the first few months of treatment, the dosage must be checked and adjusted particularly often.

In patients with cerebral spasticity, the maintenance dosages reported during long-term therapy with continuous intrathecal infusion of Baclofen range from 22 to 1400microgram of baclofen per day, with mean daily doses of 276microgram after an observation period of 1year and 307microgram after 2years. Children under 12years of age usually require lower dosages (range: 24 to 1199microgram/day; mean: 274microgram/day).

If technically possible for the pump, once a constant daily dosage is reached and the antispastic action is stabilised, it can be attempted to adapt the administration to the daily rhythm of the spasticity. For example, if spasms occur more frequently at night, this may require a 20% increase in the hourly infusion delivery rate. Changes in the infusion rate should be programmed so that they start 2hours before the desired clinical effect.

Throughout the period of treatment, regular checks in the treatment centre for the tolerability of Baclofen and for signs of infection are necessary at least at monthly intervals. The functioning of the infusion system must be checked regularly. A local infection or a malfunction of the catheter can cause interruption of the intrathecal delivery of baclofen with life-threatening consequences (see section 4.4).

The necessary concentration of baclofen when filling the pump depends on the total daily dose and on the rate of delivery of the pump. If baclofen concentrations other than 0.05mg/ml, 0.5mg/ml or 2mg/ml are required, Baclofen must be diluted under aseptic conditions with sterile preservative-free sodium chloride solution for injections. The instructions of the pump manufacturer should be observed here.

About 5% of patients may show a need for an increased dosage due to a loss of efficacy (development of tolerance) during long-term treatment. As described in the literature, a baclofen-free interval of 10 to 14days in which morphine sulphate without preservatives is administered intrathecally will counteract this development of tolerance. After this interval, responsiveness to the treatment with Baclofen may again be possible. The therapy should then be resumed at the initial dosage for the continuous infusion, and the dosage must be re-titrated in order to avoid adverse events due to overdosing. This should again be performed under inpatient conditions.

Special patient groups

In patients with slowed CSF circulation due, for example, to blockage caused by inflammation or trauma, the delayed migration of Baclofen can reduce the antispastic efficacy and boost the adverse reactions (see section 4.3).

In patients with impaired renal function, the dosage may need to be reduced to take account of the clinical condition or the level of reduced renal clearance.

Paediatric population

Maintenance Therapy

The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of “paralysis” on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis.

In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of Baclofen ranges from 25 to 200 mcg/day (median dose: 100 mcg/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.

The safety and efficacy of Baclofen for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established (also see section 4.4

Elderly patients

As part of clinical studies, some patients over 65years of age have been treated with Baclofen without specific problems being observed. Experience with Baclofen tablets shows, however, that adverse reactions can occur more frequently in this patient group. Elderly patients should therefore be monitored carefully for the development of adverse reactions.

Discontinuation of treatment

No specific limit to the duration of treatment is foreseen.

Except in emergencies due to overdosing or following development of serious adverse reactions, the treatment should always be discontinued by gradual reduction in the dosage. Baclofen must not be abruptly discontinued. In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases these may progress to seizures/status epilepticus, rhabdomyolysis, multiorgan failure and death (see section 4.4).

Abrupt discontinuation of Baclofen, especially at doses above the normal range, can lead to an intolerable increase in spasticity. Abrupt discontinuation of Baclofen tablets has also been followed by confusion, sensory disturbances, disturbed mood states with hallucinations, seizures/status epilepticus, and sometimes increased spasticity, particularly after long-term therapy.

Withdrawal symptoms

In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases these may progress to seizures/status epilepticus, rhabdomyolysis, multiorgan failure and death (see section 4.4).

Discontinuation symptoms can possibly be confused with poisoning symptoms. They also require inpatient admission of the patient.

Therapy in the event of occurrence of withdrawal symptoms

A rapid correct diagnosis and treatment in an emergency medical or intensive care unit are important to prevent the possibly life-threatening central nervous and systemic effects of withdrawal of intrathecal baclofen (see section 4.4).

4.3 Contraindications

Baclofen must not be administered in case of:

- hypersensitivity to the active substance or to any of the excipients (see section 6.1),

- therapy-resistant epilepsy.

Baclofen should be administered only into the subarachnoid space. Baclofen must not be administered by the intravenous, intramuscular, subcutaneous or epidural routes.

4.4 Special Warnings And Precautions For Use

Baclofen may be administered only with special caution to patients with:

- impaired CSF circulation due to passage constriction,

- epilepsy or other cerebral seizure illnesses,

- bulbar paralytic symptoms or partial paralysis of the respiratory musculature,

- acute or chronic confusional states,

- psychotic states, schizophrenia or Parkinson's disease,

- a history of dysreflexia of the autonomic nervous system,

- cerebrovascular and respiratory failure,

- pre-existing hypertension of the bladder sphincter,

- impaired renal function,

- peptic ulcers,

- severe hepatic dysfunction.

For patients with spasticity due to head injury, it is recommended not to proceed to long-term Baclofen therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of Baclofen in the paediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use of Baclofen in children under the age of four years.

The testing, implantation and dosage-titration phases of the intrathecal treatment must be performed in hospital under close medical supervision by suitably qualified doctors in centres with specific experience in order to ensure the continuous monitoring of the patients.

Owing to possible life-threatening events or severe adverse reactions, suitable intensive medical care facilities should be immediately available. Suitable precautionary measures must be taken before the start of treatment.

After refilling the pump, the patient must be supervised for 24 hours. A doctor must be rapidly accessible during this period.

In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect, and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases may progress to seizures / status epilepticus, rhabdomyolysis, multiple organ failure and death.

In order to prevent abrupt discontinuation of intrathecal administration of baclofen, special attention should be paid to the correct programming and monitoring of the infusion system, to the time schedules and procedures for refilling the pump and to the alarm signals of the pump. The patients and their caregivers must be instructed about the need to observe the set appointments for refilling and about the early symptoms of baclofen withdrawal. Particular attention must be paid to patients with an evident risk (e.g., patients with spinal cord injuries in the region of the sixth thoracic vertebra or higher, patients who have difficulty making themselves understood, or patients who already have a history of exhibiting withdrawal symptoms after discontinuing oral or intrathecal baclofen).

The manufacturers of infusion systems give specific instructions for the programming and refilling of the pumps, and these must be followed exactly. Experience is available only for the use of SynchroMed infusion systems. Confirmed experience with other implantable pump systems is not available.

Preconditions for treatment with Baclofen infusion solution include the ability to tolerate and respond to the single intrathecal injection of a dose of up to 100 microgram of baclofen as a bolus injection in the form of Baclofen 0.05mg/1 ml. Before the start of treatment with Baclofen, any unsatisfactory treatment with other antispastic medications should be tailed off.

Medical Support

The infusion system should not be implanted before the reaction of the patient to the single intrathecal injections of Baclofen 0.05mg/1ml is sufficiently established. The first intrathecal administration, the implantation of the infusion system, and the first infusion and dosage-titration of Baclofen are associated with risks such as CNS suppression, cardiovascular collapse and respiratory failure. These steps must therefore be performed under in-patient conditions with the availability of intensive medical care, and the instructions on dosage must be observed. The necessary facilities and support for immediate resuscitation in cases of life-threatening symptoms of severe overdosing should be available. The treating doctor must have specific experience in dealing with intrathecal administration and related infusion systems.

Monitoring the patients

After surgical implantation of the pump and particularly during the initial phase of pump activity and on changing the baclofen concentration or the infusion rate, the patient must be monitored particularly closely until his condition is stable. The treating doctor, the patient and the hospital staff as well as other persons involved in the care of the patient must be adequately informed about the risks of this method of treatment. In particular, the symptoms of overdosing or sudden withdrawal, the measures to be taken in these cases, and the care of the pump and of the implantation site must be known.

Implantation of the pump

Prior to implantation of the pump, patients should be free from infection, since an infection increases the risks of surgical complications. Moreover, a systemic infection may complicate attempts to adjust the dose.

Refilling the pump reservoir

The pump reservoir is to be re-filled by specially trained doctors according to the instructions given by the pump manufacturer. Re-fill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in recurrence of severe spasticity (see Discontinuation phenomena section).

This re-filling should be performed under strictly aseptic conditions in order to prevent contamination by microorganisms and infections. Every re-filling and every manipulation of the pump reservoir should be followed by an observation phase appropriate for the clinical situation. Extreme caution is indicated when filling an implanted pump that possesses an access port with direct access to the intrathecal catheter. Injection via the access port directly into the catheter can cause life-threatening overdosing.

Additional notes on dosage adjustment

Occasionally a certain level of spasticity is necessary to maintain body posture and balance or other functions. In order to avoid excessive weakness and thus to prevent the patient from falling over, Baclofen should be administered with care in these cases. A certain level of muscle tone and occasional spasms may also be necessary to support circulatory function and prevent deep-vein thrombosis.

Discontinuation phenomena

Abrupt discontinuation of Baclofen, regardless of cause, may manifest itself in increased spasticity as a rebound effect, pruritis, paraesthesia (tingling or burning) and hypotension. This can lead to sequelae such as a hyperactive state with rapid and uncontrolled spasms, to elevated body temperature, and to symptoms similar to those of a malignant neuroleptic syndrome such as changes in mental state and muscle rigidity. In rare cases these symptoms have developed further to seizures/ status epilepticus, muscle degradation (rhabdomyolysis), clotting disorders (coagulopathy), multiple organ failure and death.

All patients receiving intrathecal baclofen therapy are potentially at risk for abrupt withdrawal. For this reason, the patients and their caregivers must be informed about the need to observe the set appointments for re-filling the pump and be instructed about the signs and symptoms of baclofen withdrawal, especially those that occur in an early phase.

The early symptoms of baclofen withdrawal include recurrence of the spasticity originally present, itching, low blood pressure and paraesthesia. Some clinical signs of advanced withdrawal syndrome resemble those of autonomic dysreflexia, infection or sepsis, malignant hyperthermia, malignant neuroleptic syndrome or other conditions that accompany a hypermetabolic state or extensive rhabdomyolysis.

Other symptoms of abrupt discontinuation can be: hallucinations, psychotic, manic or paranoid states, severe headaches and sleeplessness. An autonomic crisis with heart failure has been observed in one case of a patient with a syndrome resembling stiff-man syndrome.

In most cases the withdrawal symptoms set in within hours or a few days after interruption of the intrathecal administration. Common reasons for the abrupt interruption of intrathecal administration are malfunctions of the catheter (especially problems with the connection), an insufficient amount of infusion solution in the reservoir, or a discharged battery in the pump. In some cases, human error may also be involved. In order to prevent abrupt interruption of intrathecal administration of baclofen, particular care should be paid to the programming and the monitoring of the infusion system, the time schedule and procedure for re-filling the pump and the alarm signals of the pump.

Therapy of discontinuation/withdrawal symptoms

Rapid and correct confirmation of the diagnosis and treatment in an emergency medical or intensive care unit are important to prevent the possibly life-threatening CNS and systemic effects of withdrawal of intrathecal baclofen. The recommended treatment is resumption of the intrathecal baclofen administration at the same or approximately the same dosage as before interruption of the intrathecal baclofen delivery. However, if intrathecal baclofen administration can be resumed only after a delay, treatment with GABA-agonists such as oral or enteral baclofen or oral, enteral or intravenous benzodiazepines can prevent the potentially fatal sequelae. However, there is no guarantee that mere administration of oral or enteral baclofen is sufficient to prevent the progression of the symptoms of withdrawal of intrathecal baclofen.

Baclofen 10 mg/5 ml solution for infusion contains less than 1 mmol sodium (23 mg) per maximum dose of 1 ml (corresponding to 2 mg baclofen), see section 4.2.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions studies with other medications have been performed.

Experience so far with the use of Baclofen in combination with other medications is not sufficient to predict interactions in individual cases.

Baclofen should not be administered concomitantly with other antispastic agents, so as to avoid possible adverse reactions.

The concomitant administration of Baclofen and other medications that have a suppressing effect on functions of the central nervous system can enhance the action of Baclofen. In particular, the concomitant intake of alcohol should be avoided as the interactions with alcohol are unpredictable.

When taken concomitantly with Baclofen tablets, some specific medications for the treatment of depression (tricyclic antidepressants) can potentiate the effect, and as a result considerable muscle relaxation may occur. For this reason, such an interaction during concomitant administration of Baclofen and tricyclic antidepressants cannot be excluded.

The combination of Baclofen tablets and antihypertensive medication can result in an enhanced reduction in blood pressure. For this reason, blood pressure should be checked regularly in the event of concomitant administration of Baclofen and medications for lowering blood pressure. If applicable, the dosage of the antihypertensive medication must be reduced.

When Baclofen is combined with morphine, a drop in blood pressure has occurred in one case. It cannot be excluded that in such cases respiratory disturbances or CNS disturbances may also occur. For this reason, an increased risk of these disturbances should be borne in mind during concomitant administration of opiates or benzodiazepines.

There is hitherto no information on the concomitant administration of Baclofen with other intrathecally administered medications.

4.6 Pregnancy And Lactation

Pregnancy

No experience is available relating to the use of Baclofen during pregnancy. Baclofen crosses the placenta and has shown reproductive toxicity (see section 5.3). Baclofen should not be used during pregnancy, unless the advantages of the therapy for the mother outweigh the possible risks to the child.

Lactation

Baclofen is excreted in breast milk. No statement concerning breast milk concentration can be made as there is insufficient data available. Baclofen should not be used during lactation, unless the advantages of the therapy for the mother outweigh the possible risks to the child.

4.7 Effects On Ability To Drive And Use Machines

The ability to drive or operate machinery may be considerably impaired during treatment with Baclofen. Alcohol consumption increases this impairment still further.

In patients treated with inthrathecal baclofen, the ability to continue driving or operating complex machinery should be routinely evaluated by the treating physician.

4.8 Undesirable Effects

Adverse reactions (Table 1) are ranked under headings of frequency, the most frequent first, using the following convention: very common (

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

Table 1

Metabolism and nutrition disorders
Common:	Decreased appetite.
Uncommon:	Dehydration.
Psychiatric disorders
Common:	Depression, Confusional state, Disorientation, Agitation, Anxiety.
Uncommon:	Suicidal ideation, Paranoia, Hallucinations, Dysphoria.
Nervous system disorders
Very common:	Somnolence.
Common:	Respiratory depression, Convulsion, Lethargy, Dysarthria, Headache, Paraesthesia, Insomnia, Sedation, Dizziness. Convulsion and headache occur more frequently in patients with cerebral spasticity.
Uncommon:	Ataxia, Hypothermia, Dysphagia, Memory impairment, Nystagmus.
Eye disorders
Common:	Accommodation disorders with vision blurred or diplopia.
Cardiac disorders
Uncommon:	Bradycardia.
Vascular disorders
Common:	Orthostatic hypotension
Uncommon:	Deep vein thrombosis, Hypertension, Flushing, Pallor.
Respiratory, thoracic and mediastinal disorders
Common:	Aspiration Pneumonia, Dyspnoea, Bradypnoea.
Gastrointestinal disorders
Common:	Vomiting, Constipation, Diarrhoea, Nausea, Dry mouth, Salivary hypersecretion Nausea and vomiting occur more frequently in patients with cerebral spasticity
Uncommon:	Ileus, Hypogeusia.
Skin and subcutaneous tissue disorders
Common:	Urticaria, Pruritus.
Uncommon:	Alopecia, Hyperhidrosis.
Musculoskeletal and connective tissue disorders
Very common:	Hypotonia.
Common:	Hypertonia, Muscular weakness.
Renal and urinary disorders
Common:	Urinary retention, Urinary incontinence. Urinary retention occurs more frequently in patients with cerebral spasticity.
Reproductive system and breast disorders
Common:	Sexual dysfunction.
General disorders and administration site conditions
Common:	Oedema peripheral, Face oedema, Pain, Pyrexia, Chills.

In approximately 5% of female patients with multiple sclerosis who have been treated with Baclofen tablets for up to one year, ovarian cysts have been established by palpation. In most cases, these cysts disappeared spontaneously despite continuation of therapy. It is known that a part of the healthy female population develop ovarian cysts spontaneously.

A reliable causal connection between the observed adverse events and the administration of Baclofen is not always possible as some of the observed adverse events could also be symptoms of the underlying illness being treated. Particularly frequently occurring adverse events such as dizziness, light-headedness, somnolence, headache, nausea, drop in blood pressure, and muscle weakness are usually due to the medication.

Adverse events due to the infusion system

These can include dislocation/kinking/rupture (tearing) of the catheter, infection of the implantation site, meningitis, septicaemia, pump-pocket seroma and haematoma with a possible risk of inflammation, failure of the pump function and CSF leakage, as well as skin perforation after a long time, and overdosing or underdosing due to incorrect handling.

4.9 Overdose

At the first signs of overdosing with Baclofen, the patient should be admitted to inpatient care if being treated as an outpatient.

Attention should be paid to symptoms of overdosing throughout the period of treatment, but especially during the test phase and the dosage adjustment phase and on restarting Baclofen after a pause in treatment.

Overdosing can occur, for example, as a result of accidental delivery of the contents of the catheter during checking of the patency or position of the catheter. Other possible causes are errors in the programming, extremely rapid dosage increment, concurrent oral administration of baclofen or malfunction of the pump.

In one case, an adult patient showed signs of severe overdosing (coma) after injection of a single dose of 25microgram of baclofen (Baclofen). Conversely, daily dosages of 4000microgram have been required and tolerated in isolated cases (German studies). The lowest lethal dose reported in German studies is 4000microgram, and the highest recorded dose survived without sequelae is 20000microgram of baclofen (Baclofen).

Symptoms of poisoning

Increasing muscle hypotension, dizziness, sedation, convulsion, loss of consciousness, salivary hypersecretion, nausea and vomiting.

Respiratory depression, apnoea and coma may occur in acute massive overdosing.

Therapy in overdosing

There is no known specific antidote for the treatment of overdosing with Baclofen. In general the following measures should be performed:

• Removal as rapidly as possible of the remaining baclofen solution from the pump.

• Patients with respiratory depression should be intubated until baclofen has been eliminated.

There are observations that indicate that intravenously administered physostigmine can counteract the actions on the central nervous system, especially drowsiness and respiratory depression.

Administration of a total intravenous dose of 1 to 2mg of physostigmine over 5 to 10minutes may be attempted in adult patients. During this time, the patients should be monitored closely, especially for signs of induction of seizures, bradycardia and cardiac conduction disturbances. If the therapy proves effective, repeat doses of 1mg of physostigmine at intervals of 30 to 60minutes can be administered to maintain respiration and consciousness.

In children, a dose of 0.02mg of physostigmine per kg bodyweight can be administered intravenously at a rate not exceeding 0.5mg/minute. The dose can be repeated at intervals of 5 to 10minutes until the therapeutic effect is achieved. The maximum dose should not exceed 2mg.

Physostigmine on its own may not be sufficient to treat high overdoses, and in these cases the patient must be artificially ventilated.

If lumbar puncture is not contraindicated, 30 to 40ml of CSF may be drawn off in the initial phase of poisoning in order to lower the concentration of baclofen in the CSF.

Support of the cardiovascular function. If spasms occur, diazepam intravenous should be administered carefully.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: muscle-relaxants, other centrally acting agents, ATC code: M03BX01

Baclofen is a p-chlorophenyl derivative of gamma-aminobutyric acid (GABA), which is ubiquitous in the central nervous system and is the most important inhibitory transmitter in the CNS. The exact mechanism of action of baclofen is not yet fully elucidated. It stimulates GABA_B-receptors that are located pre- and postsynaptically. Its action is based on boosting of the presynaptic inhibition starting mainly in the spinal marrow, which leads to damping of the stimulus transmission. This causes a reduction in the spastic muscle tone and in the pathological mass reflexes in spasticity. Being a centrally acting muscle relaxant, baclofen does not affect the neuromuscular stimulus transmission.

In humans as in animals, baclofen can cause general suppression of the central nervous system, and this can lead to sedation and somnolence as well as to respiratory and cardiovascular suppression.

5.2 Pharmacokinetic Properties

The systemic availability of baclofen after intrathecal administration (Baclofen) is considerable less than after oral administration (Baclofen tablets).

When considering the pharmacokinetic data on Baclofen, the effects of the slow CSF circulation should be taken into account.

Absorption

Infusion directly into the spinal subarachnoid space circumvents absorption processes and allows access to the receptor sites in the posterior horn of the spinal cord.

The direct delivery of baclofen to the cerebrospinal space allows effective treatment of the spasticity with doses that are at least 100 times lower than those of oral therapy (Baclofen tablets).

Distribution

After a single intrathecal bolus injection/rapid infusion, the distribution volume calculated from the concentration in the CSF ranges from 22 to 157ml. The mean of about 75ml corresponds approximately to the human CSF volume, and indicates that it is this in which the baclofen is mainly distributed. With continuous intrathecal infusion of daily doses of between 50 to 1200 microgram, steady-state concentrations of baclofen in the CSF of the lumbar region of 130 to 1240 nanogram/ml are reached within 1 to 2 days. In the steady state with continuous intrathecal infusion of daily doses between 95 to 190 microgram, a mean baclofen concentration gradient from lumbar to cisternal of 4:1 (range 8.7:1-1.8:1) is found. This is independent of the body position of the patient. All three strengths of baclofen solution (density: 1.003 ± 0.001 g/cm³ at 23°C) are practically isobaric to human CSF (density: 1.006-1.008 g/cm³). The baclofen plasma concentrations under intrathecal infusion of clinically used doses of baclofen are below 5 nanogram/ml (

Elimination

The elimination half-life from the CSF after administration of a single intrathecal bolus injection/ rapid infusion of 50 to 135 microgram of baclofen is 1 to 5 hours. Both after a single bolus injection and after continuous infusion into the spinal subarachnoid space using an implanted pump, the mean clearance from the CSF is about 30 ml/hour (corresponding to the physiological turnover rate of the CSF). Thus the amount of baclofen infused over 24 hours is eliminated almost completely with the CSF over the same period of time. Systemic baclofen is eliminated almost completely renally in the unaltered form. A metabolite (beta-(p-chlorophenyl)-gamma-hydroxybutyric acid) formed in small amounts in the liver by oxidative desamination is inactive. Investigations suggest baclofen is not metabolised in the CSF. Other routes of elimination are not considered significant according to the information currently available.

From animal experiments it is evident that the active substance cumulates in the CSF after administration of high doses. It has not been investigated to what extent this finding is relevant for humans and what consequences should be expected.

5.3 Preclinical Safety Data

Histological investigations in studies with continuous intrathecal infusion of baclofen to rats (2

Baclofen was not mutagenic in in-vivo and in-vitro studies.

A 2-year study on rats with oral administration showed that baclofen is not carcinogenic. A dose-dependent rise in the incidence of ovarian cysts and a less pronounced rise in the incidence of enlarged and/or haemorrhagic adrenal glands was observed in female rats treated for two years with baclofen. The findings suggest endocrine effects of baclofen, and the basis for this could be an action on hypothalamic hormones. These effects occur in test animals (and presumably also in humans) possibly only in conjunction with age-related hormonal changes.

After a dose equivalent to about 13 times the maximum oral dose recommended for humans, rat foetuses showed a raised incidence of omphaloceles. This malformation was not observed in mice or rabbits.

Baclofen had no effect on the fertility of female rats. Possible effects on male fertility have not been investigated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Water for injections

6.2 Incompatibilities

Baclofen solutions for infusions must not be mixed with other infusion or injection solutions except those mentioned in section 6.6.

6.3 Shelf Life

Shelf life in unopened containers:

Baclofen 10 mg/5 ml solution for infusion: 18 months

The product should be used immediately after opening.

Shelf life after dilution:

Chemical and physical in-use stability has been demonstrated for 2 months at 37°C.

6.4 Special Precautions For Storage

This product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Baclofen 10 mg/5 ml solution for infusion:

Clear, colourless ampoules of glass type I (Ph.Eur.) containing 5 ml of solution for infusion.

Packs with 1 or 5 ampoules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unrequired fraction must be destroyed.

If required, Baclofen 10mg/20ml and 10mg/5ml solution for infusion may be diluted under aseptic conditions with sterile, preservative-free sodium chloride solution for injection.

7. Marketing Authorisation Holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing Authorisation Number(S)

Baclofen 10 mg/5 ml solution for infusion - PL 31750/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

15 /02/2010

10. Date Of Revision Of The Text

Wednesday, March 28, 2012

Astramorph PF

Generic Name: morphine (Injection route)

MOR-feen

Injection route(Solution)

Misuse or erroneous substitution of Infumorph(TM) 200 or 500 (10 or 25 mg/mL, respectively) for Duramorph(TM) (0.5 or 1 mg/mL) may result in overdose, seizures, respiratory depression, or possibly death. With the use of morphine sulfate, there is a risk of severe adverse effects when the epidural, intrathecal, or catheter implantation route of administration is employed. Monitor patients closely and have naloxone injection and resuscitative equipment immediately available. Do not use Infumorph(TM) for single-dose intravenous, intramuscular, or subcutaneous administration due to the possible risk of overdose. For Duramorph(TM), the intrathecal dosage is usually 1/10 that of epidural dosage .

Commonly used brand name(s)

In the U.S.

Astramorph PF

Duramorph

Infumorph

Available Dosage Forms:

Solution

Injectable

Therapeutic Class: Analgesic

Chemical Class: Opioid

Uses For Astramorph PF

Morphine injection is used to relieve moderate to severe pain. It may also be used before or during surgery with an anesthetic (medicine that puts you to sleep). Morphine belongs to the group of medicines called narcotic analgesics (pain medicines). It acts on the central nervous system (CNS) to relieve pain.

When a narcotic medicine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

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

Before Using Astramorph PF

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 performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of morphine injection in children 1 month of age and older. Safety and efficacy in infants younger than 1 month of age have not been established. Morphine injections into the back are not recommended for children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of morphine injection in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or lung problems, which may require caution and an adjustment in the dose for patients receiving morphine injection.

Pregnancy

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

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Brofaromine

Clorgyline

Furazolidone

Iproniazid

Isocarboxazid

Lazabemide

Linezolid

Moclobemide

Naltrexone

Nialamide

Pargyline

Phenelzine

Procarbazine

Rasagiline

Selegiline

Toloxatone

Tranylcypromine

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.

Adinazolam

Alfentanil

Alprazolam

Amobarbital

Anileridine

Aprobarbital

Bromazepam

Brotizolam

Buprenorphine

Butabarbital

Butalbital

Butorphanol

Carisoprodol

Chloral Hydrate

Chlordiazepoxide

Chlorpromazine

Chlorzoxazone

Cimetidine

Clobazam

Clonazepam

Clorazepate

Codeine

Dantrolene

Dezocine

Diazepam

Estazolam

Ethchlorvynol

Fentanyl

Flunitrazepam

Fluphenazine

Flurazepam

Halazepam

Hydrocodone

Hydromorphone

Ketazolam

Levorphanol

Lorazepam

Lormetazepam

Medazepam

Meperidine

Mephenesin

Mephobarbital

Meprobamate

Metaxalone

Methocarbamol

Methohexital

Midazolam

Morphine

Morphine Sulfate Liposome

Nalbuphine

Nitrazepam

Nordazepam

Opium

Oxazepam

Oxycodone

Oxymorphone

Pentazocine

Pentobarbital

Perphenazine

Phenobarbital

Prazepam

Prochlorperazine

Promazine

Promethazine

Propoxyphene

Quazepam

Remifentanil

Secobarbital

Sodium Oxybate

Sufentanil

Tapentadol

Temazepam

Thiethylperazine

Thiopental

Thioridazine

Triazolam

Trifluoperazine

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

Cyclosporine

Esmolol

Gabapentin

Rifampin

Somatostatin

Yohimbine

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. 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 is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Ethanol

Proper Use of morphine

This section provides information on the proper use of a number of products that contain morphine. It may not be specific to Astramorph PF. Please read with care.

A nurse or other trained health professional will give you this medicine in a hospital. This medicine may be given as a shot under the skin, as a shot into one of your muscles, or through a needle placed in one of your veins. It can also be given through a needle or catheter into your back.

Your doctor will give you a few doses of this medicine until your condition improves, and then switch you to an oral medicine that works the same way. If you have any concerns about this, talk to your doctor.

Precautions While Using Astramorph PF

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

This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before you or your child take any of the medicines listed above while you are using this medicine.

This medicine may be habit-forming. If you or your child feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you or your child to take laxatives, drink a lot of fluids, or increase the amount of fiber in the diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

Dizziness, lightheadedness, or fainting may occur when you or your child get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine may make you dizzy, drowsy, confused, or disoriented. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you or your child are using this medicine. Serious unwanted effects can occur if certain medicines are given together with morphine injection.

If you or your child have been using this medicine regularly for several weeks or longer, do not suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

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

Astramorph PF 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

Difficult or troubled breathing

irregular, fast or slow, or shallow breathing

pale or blue lips, fingernails, or skin

shortness of breath

very slow breathing

Incidence not known

Blurred vision

convulsions

decrease in frequency of urination

decrease in the amount of urine

difficulty in passing urine (dribbling)

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

painful urination

sweating

unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Bluish lips or skin

dizziness

fainting

irregular heartbeat

lightheadedness

low blood pressure or pulse

slow heartbeat

unconsciousness

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

Incidence not known

Absent, missed, or irregular menstrual periods

anxiety

confusion

decreased interest in sexual intercourse

delusions

depersonalization

difficulty having a bowel movement (stool)

false or unusual sense of well-being

hallucinations

headache

inability to have or keep an erection

itching skin

loss in sexual ability, desire, drive, or performance

menstrual changes

nausea and vomiting

stopping of menstrual bleeding

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: Astramorph PF 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 Astramorph PF resources

Astramorph PF Side Effects (in more detail)
Astramorph PF Use in Pregnancy & Breastfeeding
Astramorph PF Drug Interactions
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0 Reviews for Astramorph PF - Add your own review/rating

Astramorph PF Prescribing Information (FDA)

Astramorph PF Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Morphine Concentrate MedFacts Consumer Leaflet (Wolters Kluwer)

Avinza Consumer Overview

Avinza Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Avinza Prescribing Information (FDA)

Infumorph Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Kadian Prescribing Information (FDA)

Kadian Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Kadian Consumer Overview

MS Contin Prescribing Information (FDA)

MS Contin Sustained-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

MS Contin Consumer Overview

Morphine Sulfate Monograph (AHFS DI)

Oramorph SR Prescribing Information (FDA)

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Pain

Friday, March 23, 2012

Pediatric Multivitamin/Minerals Chewables

Pronunciation: MUL-ti-VYE-ta-min/MIN-er-als
Generic Name: Pediatric Multivitamin/Minerals
Brand Name: Examples include Cerovite Jr and Flintstones Gummies

Pediatric Multivitamin/Minerals Chewables are used for:

Treating or preventing low levels of vitamins and minerals in the body. It may also be used for other conditions as determined by your doctor.

Pediatric Multivitamin/Minerals Chewables are a vitamin and mineral supplement. It works by providing extra vitamins and minerals to the body when you do not get enough from your diet.

Do NOT use Pediatric Multivitamin/Minerals Chewables if:

you are allergic to any ingredient in Pediatric Multivitamin/Minerals Chewables

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

Before using Pediatric Multivitamin/Minerals Chewables:

Some medical conditions may interact with Pediatric Multivitamin/Minerals Chewables. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

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

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

if you have allergies to medicines, foods, or other substances (eg, soy)

if you have anemia, liver problems, metabolism problems, or phenylketonuria

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

Acitretin, anticoagulants (eg, warfarin), or fluorouracil because the risk of their side effects may be increased by Pediatric Multivitamin/Minerals Chewables

Doxycycline, hydantoins (eg, phenytoin), levodopa, penicillamine, or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Pediatric Multivitamin/Minerals Chewables

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

How to use Pediatric Multivitamin/Minerals Chewables:

Use Pediatric Multivitamin/Minerals Chewables as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Pediatric Multivitamin/Minerals Chewables by mouth with or without food.

Chew well before swallowing.

If your brand of Pediatric Multivitamin/Minerals Chewables contains iron, do not take an antacid within several hours before or after you take Pediatric Multivitamin/Minerals Chewables.

If you are also taking a bisphosphonate (eg, alendronate), cefdinir, methyldopa, a quinolone antibiotic (eg, ciprofloxacin), or a tetracycline antibiotic (eg, minocycline), ask your doctor or pharmacist how to take them with Pediatric Multivitamin/Minerals Chewables.

If you miss a dose of Pediatric Multivitamin/Minerals Chewables for 1 or more days, there is no cause for concern. If your doctor recommended that you take it, try to remember your dose every day.

Ask your health care provider any questions you may have about how to use Pediatric Multivitamin/Minerals Chewables.

Important safety information:

Do not take large doses of vitamins while you use Pediatric Multivitamin/Minerals Chewables unless your doctor tells you to.

Some brands of Pediatric Multivitamin/Minerals Chewables contain soy. If you are allergic to soy products, ask your pharmacist if your brand contains soy.

Some of these products contain phenylalanine. If you must have a diet that is low in phenylalanine, ask your pharmacist if it is in your product.

Pediatric Multivitamin/Minerals Chewables should not be used in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed. These children may also have an increased risk of choking on Pediatric Multivitamin/Minerals Chewables.

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

Possible side effects of Pediatric Multivitamin/Minerals Chewables:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with this product. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Pediatric Multivitamin/Minerals Chewables:

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

General information:

If you have any questions about Pediatric Multivitamin/Minerals Chewables, please talk with your doctor, pharmacist, or other health care provider.

Pediatric Multivitamin/Minerals Chewables are to be used only by the patient for whom it is prescribed. Do not share it with other people.

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

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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Pediatric Multivitamin/Minerals resources

Pediatric Multivitamin/Minerals Use in Pregnancy & Breastfeeding
Pediatric Multivitamin/Minerals Drug Interactions
Pediatric Multivitamin/Minerals Support Group
4 Reviews for Pediatric Multivitamin/Minerals - Add your own review/rating

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Vitamin/Mineral Supplementation and Deficiency

Tuesday, March 20, 2012

Methyldopate

Dosage Form: injection
Methyldopate

HCl Injection,

USP

Methyldopate Description

Methyldopate HCl Injection, USP, is an antihypertensive agent for intravenous use. Sterile, nonpyrogenic.

Methyldopate hydrochloride [levo-3-(3,4-dihydroxyphenyl)-2-methylalanine, ethyl ester hydrochloride] is the ethyl ester of methyldopa, supplied as the hydrochloride salt with a molecular weight of 275.73. Methyldopate hydrochloride is more soluble and stable in solution than methyldopa and is the preferred form for intravenous use.

The molecular formula for Methyldopate hydrochloride is C12H17NO4·HCl and the structural formula is:

Each mL contains:

: Methyldopate Hydrochloride ......... 50 mg
: Citric Acid (Anhydrous) ................. 5 mg
: Edetate Disodium ......................... 0.5 mg
: Monothioglycerol ........................... 2 mg
: Water for Injection ......................... q.s. to 1 mL

Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.

Methyldopate - Clinical Pharmacology

Methyldopate, an antihypertensive agent, is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.

Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.

Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.

Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.

Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Pharmacokinetics and Metabolism

Methyldopate hydrochloride is the ethyl ester of methyldopa hydrochloride and possesses the same pharmacologic attributes.

Methyldopa is extensively metabolized. The known urinary metabolites are ∝-methyldopa mono-0-sulfate; 3-0-methyl-∝-methyldopa; 3,4-dihydroxyphenylacetone; ∝-methyldopamine; 3-0-methyl-∝-methyldopamine and their conjugates.

Following intravenous administration of Methyldopate hydrochloride a decrease in blood pressure may occur in four to six hours and last 10 to 16 hours.

Approximately 49 percent of the dose of Methyldopate hydrochloride is excreted in the urine as methyldopa and its mono-0-sulfate. The renal clearance of methyldopa following Methyldopate hydrochloride is about 156 mL/min in normal subjects and is diminished in renal insufficiency. Following Methyldopate hydrochloride injection the plasma half-life of methyldopa is 90-127 minutes. Approximately 17 percent of a dose of Methyldopate hydrochloride given to normal subjects appears in plasma as free methyldopa.

Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.

Indications and Usage for Methyldopate

Hypertension, when parenteral medication is indicated. The treatment of hypertensive crises may be initiated with Methyldopate HCl Injection.

Contraindications

Methyldopate hydrochloride is contraindicated in patients:

: -with active hepatic disease, such as acute hepatitis and active cirrhosis.
: -with liver disorders previously associated with methyldopa therapy (see WARNINGS).
: -with hypersensitivity to any component of this product, including sulfites (see WARNINGS).
: -on therapy with monoamine oxidase (MAO) inhibitors.

Warnings

It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.

With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 gram or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.

Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.

Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.

If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.

When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.

Should the need for transfusion arise in a patient receiving methyldopa, both a direct and indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.

Occasionally, fever has occurred within the first three weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.

Rarely fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determination of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.

Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.

Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

General

Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction (see “WARNINGS”).

Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.

A paradoxical pressor response has been reported with intravenous administration of Methyldopate HCl Injection.

Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.

Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.

Laboratory Tests

Blood count, Coombs test, and liver function tests are recommended before initiating therapy and at periodic intervals (see “WARNINGS”).

Drug Interactions

When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.

Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.

When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.

Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS.

Drug/Laboratory Test Interactions

Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported.

Since methyldopa causes fluorescence in urine samples at the same wavelengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).

Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatic exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.

Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Methyldopate hydrochloride; nor have evaluations of this ester's mutagenic potential or potential to affect fertility been carried out.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Methyldopate HCl. It is also not known whether Methyldopate HCl can affect reproduction capacity or can cause fetal harm when given to a pregnant woman. Methyldopate HCl should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.

Pediatric Use

There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients. (See DOSAGE AND ADMINISTRATION.)

Adverse Reactions

Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.

The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.

Cardiovascular: Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, paradoxical pressor response with intravenous use, orthostatic hypotension (decrease daily dosage), edema and weight gain, bradycardia.

Digestive: Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or ``black′′ tongue, nausea, constipation, distension, flatus, dryness of mouth.

Endocrine: Hyperprolactinemia.

Hematologic: Bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; positive tests for antinuclear antibody, LE cells, and rheumatoid factor, positive Coombs tests.

Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver function test (see “WARNINGS”).

Hypersensitivity: Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.

Nervous System/Psychiatric: Parkinsonism, Bell's palsy, decreased mental acuity, choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, lightheadedness, paresthesias.

Metabolic: Rise in BUN.

Musculoskeletal: Arthralgia, with or without joint swelling; myalgia.

Respiratory: Nasal stuffiness.

Skin: Toxic epidermal necrolysis, rash.

Urogenital: Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.

Overdosage

Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting).

In the event of overdosage, symptomatic and supportive measures should be employed. Management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.

Sympathomimetic drugs [e.g., levarterenol, epinephrine, ARAMINE* (Metaraminol Bitartrate, MSD)] may be indicated.

The acute intravenous LD50 of Methyldopate HCl in the mouse is 321 mg/kg.

Methyldopate Dosage and Administration

Methyldopate HCl Injection when given intravenously in effective doses, causes a decline in blood pressure that may begin in four to six hours and last 10 to 16 hours after injection.

Add the desired dose of Methyldopate HCl Injection to 100 mL of Dextrose Injection 5%, USP. Alternatively the desired dose may be given in 5% dextrose in water in a concentration of 100 mg/10 mL. Give this intravenous infusion slowly over a period of 30 to 60 minutes.

Adults: The usual adult dosage intravenously is 250 mg to 500 mg at six hour intervals as required. The maximum recommended intravenous dose is 1 gram every six hours.

When control has been obtained, oral therapy with tablets may be substituted for intravenous therapy, starting with the same dosage schedule used for the parenteral route. The effectiveness and anticipated responses are described in the circular for tablets.

Since Methyldopate has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.

Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 grams of methyldopa daily.

Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.

Pediatric Patients: The recommended daily dosage is 20 to 40 mg/kg of body weight in divided doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily, whichever is less. When the blood pressure is under control, continue with oral therapy using tablets in the same dosage as for the parenteral route. (see PRECAUTIONS, Pediatric Use.)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How is Methyldopate Supplied

Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL).

NDC 0517-8905-10 5 mL Single Dose Vial Boxes of 10

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).

Rx Only

IN8905

Rev. 11/05

MG #7604

American

Regent, Inc.

Shirley, NY 11967

PRINCIPAL DISPLAY PANEL – 5 mL Carton

Methyldopate HCl INJECTION, USP

250 mg/5 mL (50 mg/mL)

NDC 0517-8905-10

10 x 5 mL SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION

Rx Only

Each mL contains: Methyldopate HCl 50 mg, Citric Acid (Anhydrous) 5 mg, Edetate Disodium 0.5 mg, Monothioglycerol 2 mg, Water for Injection q.s. Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.

DISCARD UNUSED PORTION.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Methyldopate HYDROCHLORIDE
Methyldopate hydrochloride injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0517-8905
Route of Administration	INTRAVENOUS	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Methyldopate hydrochloride (Methyldopate)	Methyldopate hydrochloride	50 mg in 1 mL

Inactive Ingredients
Ingredient Name	Strength
citric acid anhydrous
sodium bisulfite
monothioglycerol
methylparaben
edetate disodium
PROPYLPARABEN
water

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0517-8905-10	10 VIAL In 1 BOX	contains a VIAL, SINGLE-DOSE
1		5 mL In 1 VIAL, SINGLE-DOSE	This package is contained within the BOX (0517-8905-10)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA071279	09/30/1995

Labeler - American Regent, Inc. (622781813)

Establishment
Name	Address	ID/FEI	Operations
Luitpold Pharmaceuticals, Inc.		002033710	MANUFACTURE, LABEL, PACK, STERILIZE

Revised: 10/2011American Regent, Inc.

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1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

3. Pharmaceutical Form

4. Clinical Particulars

4.1 Therapeutic Indications

4.2 Posology And Method Of Administration

4.3 Contraindications

4.4 Special Warnings And Precautions For Use

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

4.6 Pregnancy And Lactation

4.7 Effects On Ability To Drive And Use Machines

4.8 Undesirable Effects

4.9 Overdose

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

5.2 Pharmacokinetic Properties

5.3 Preclinical Safety Data

6. Pharmaceutical Particulars

6.1 List Of Excipients

6.2 Incompatibilities

6.3 Shelf Life

6.4 Special Precautions For Storage

6.5 Nature And Contents Of Container

6.6 Special Precautions For Disposal And Other Handling

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8. Marketing Authorisation Number(S)

9. Date Of First Authorisation/Renewal Of The Authorisation

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