ARO-CETAM

Levetiracetam 1500 mg/100 mL

Solution for IV infusion

DESCRIPTION

For intravenous use

Each ml contains 15 mg of levetiracetam.

Each 100 ml vial contains 1500 mg of levetiracetam.

Levetiracetam injection is antiepileptic drug available as a clear, colorless to light yellow, sterile solution (15 mg/mL) for infusion.

INDICATIONS AND USAGE

Levetiracetam is used on its own in patients from 16 years of age with newly diagnosed epilepsy, to treat a certain form of epilepsy. Levetiracetam is used for the epilepsy form in which the fits initially affect only one side of the brain, but could thereafter extend to larger areas on both sides of the brain (partial onset seizure with or without secondary generalization).

 Also Levetiracetam is used with other antiepileptic medicines in:

• Partial Onset Seizures

Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 1 month of age and older with epilepsy.

ü  Myoclonic Seizures in Patients with Juvenile MyoclonicEpilepsy

Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.

ü  Primary Generalized Tonic-ClonicSeizures

Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

DOSAGE AND ADMINISTRATION

Monotherapy

General dose in adults and adolescents (from 16 years of age) is between 1,000 mg and 3,000 mg each day.

Add-on therapy

• Partial Onset Seizures

Adults

Initially, 500 mg IV twice daily. The dose may be increased every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments as needed. Max: 3,000 mg/day. There is no evidence that doses greater than 3,000 mg/day provide additional benefit.

Adolescents 16 to 17 years

Initially, 500 mg IV twice daily. The dose may be increased every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments as needed. Max: 3,000 mg/day. There is no evidence that doses greater than 3,000 mg/day provide additional benefit.

Children and Adolescents 4 to 15 years

Initially, 10 mg/kg/dose IV twice daily. Increase the dosage every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dosage of 30 mg/kg IV twice daily. If a patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day (Max: 3,000 mg/day) in this age group.

Infants and Children 6 months to 3 years

Initially, 10 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dose of 25 mg/kg/dose IV twice daily. If a patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day in this age group.

Infants 1 to 5 months

Initially, 7 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 7 mg/kg/dose (i.e., 14 mg/kg/day) increments to the recommended dose of 21 mg/kg/dose IV twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day in this age group; the effectiveness of lower doses has not been studied.

• Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

• Primary Generalized Tonic-Clonic Seizures

Adults

Initially, 500 mg IV twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dose of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown if doses lower than 3,000 mg/day are effective.

Adolescents 16 to 17 years

Initially, 500 mg IV twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dose of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown if doses lower than 3,000 mg/day are effective.

Children and Adolescents 6 to 15 years

Initially, 10 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dosage of 30 mg/kg/dose IV twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 60 mg/kg/day are effective.

Switching from Oral Dosing

When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam.

Switching to OralDosing

At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

Ø  Preparation and Administration Instructions

Levetiracetam injection should be administered as a 15-minutes IV infusion. Consideration should also be given to the total daily fluid intake of the patient. One vial of ARO-CETAM injection contains 1500 mg levetiracetam (1500 mg/100 mL).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.

Any unused portion of the ARO-CETAM injection vial contents should be discarded.

Pediatric Patients

When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).

The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

Dosage Adjustments in Adult Patients with Renal Impairment

Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults with renal impairment are shown in Table 2. Information is unavailable for dosage adjustments in pediatric patients with renal impairment. In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment

*Following dialysis, a 250 to 500 mg supplemental dose is recommended.

COMPATIBILITY AND STABILITY

Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following:

• Sodium chloride (0.9%) injection, Lactated Ringer’s injection, Dextrose 5% injection.

• Other Antiepileptic Drugs: Lorazepam, Diazepam, Valproate sodium.

CONTRAINDICATIONS

ARO-CETAM is contraindicated in patients with hypersensitivity to levetiracetam.

WARNINGS AND PRECAUTION

Dialysis, renal disease, renal failure, renal impairment

The clearance of levetiracetam is reduced in patients with renal disease or renal impairment and is correlated with creatinine clearance. The dosage of levetiracetam should be reduced in patients with impaired renal function.

Behavioral Abnormalities and PsychoticSymptoms

Levetiracetam may cause behavioral abnormalities and psychotic symptoms. Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms.

Somnolence and Fatigue

Levetiracetam may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with Levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug- related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Coordination Difficulties

Levetiracetam may cause coordination difficulties. Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect their ability to drive or operatemachinery.

Withdrawal Seizures

Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalities

Levetiracetam may cause decreases in red blood cells count (RBC), hemoglobin, hematocrit, white blood cells count (WBC), and neutrophil count.

Increase in Blood Pressure

Monitor blood pressure in neonates, infants, and children < 4 years of age receiving levetiracetam.  Children 1 month to < 4 years who are treated with levetiracetam have a significantly higher risk of increased diastolic pressure. There was no overall difference in the mean diastolic blood pressure between treatment groups, and an increased risk was not observed in studies of older children or adults.

Seizure Control During Pregnancy

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed duringpregnancy.

POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor immediately, or go to your nearest emergency department, if you experience:

-weakness, feel light-headed or dizzy or have difficulty breathing, as these may be signs of a serious allergic (anaphylactic) reaction

-swelling of the face, lips, tongue and throat (Quincke’soedema)

-flu-like symptoms and a rash on the face followed by an extended rash with a high temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes (Drug Reaction with Eosinophilia and Systemic

Symptoms

- symptoms such as low urine volume, tiredness, nausea, vomiting, confusion and swelling in the legs, ankles or feet, as this may be a sign of sudden decrease of kidney function

-a skin rash which may form blisters andlook like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme)

-a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome)

-a more severe form of rash causing skin peeling in more than 30% of the body surface (toxic epidermal necrolysis)

-signs of serious mental changes or if someone around you notices signs of confusion, somnolence (sleepiness), amnesia (loss of memory), memory impairment (forgetfulness), abnormal behavior or other neurological signs including involuntary or uncontrolled movements. These could be symptoms of an encephalopathy.

ADVERSE REACTIONS

The most frequently reported adverse reactions were nasopharyngitis, somnolence (sleepiness), headache,

Fatigue and dizziness. At the beginning of the treatment or at dose increaseof the side effects like sleepiness, tiredness and dizziness may be more common. These effects should however decrease over time.

Very common:

-nasopharyngitis

-somnolence (sleepiness), headache

Common:

-anorexia (loss of appetite)

-depression, hostility or aggression, anxiety, insomnia, nervousness or irritability

-convulsion, balance disorder (equilibrium disorder), dizziness (sensation ofunsteadiness), lethargy (lack of energy and enthusiasm)

, tremor (involuntary trembling)

-vertigo (sensation of rotation)

-cough

-abdominal pain, diarrhea, dyspepsia (indigestion), vomiting, nausea

-rash

-asthenia/fatigue (tiredness)

Uncommon:

 -decreased number of blood platelets, decreased number of white blood cells

-weight decrease, weight increase

-suicide attempt and suicidal ideation, mental disorder, abnormal behavior, hallucination, anger, confusion,

Panic attack, emotional instability/mood swings, agitation

-amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia (impaired coordinated movements), paresthesia

a (tingling), disturbance in attention (loss of concentration)

-diplopia (double vision), vision blurred

-elevated/abnormal values in a liver function test

-hair loss, eczema, pruritus

-muscle weakness, myalgia (muscle pain)

-injury

Rare:

-infection

-decreased number of allblood celltypes

-severe allergicreactions

Quincke’soedema

-decreased blood sodium concentration

-suicide, personality disorders (behavioral problems), thinking abnormal (slow thinking, unable to concentrate)

-uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling movements, hyperkinesia (hyperactivity)

-pancreatitis

-liver failure hepatitis

-sudden decrease in kidney function

-skin rash, which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythemamultiforme), a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body surface (toxic epidermal necrolysis)

-rhabdomyolysis (breakdown of muscle tissue) and associated blood creatine phosphokinase increase.

-limp or difficulty walking.

DRUG INTERACTIONS

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications via human liver cytochrome P450 isoforms, epoxide hydrolase, UDP-glucuronidation enzymes, P-glycoprotein, or renal tubular secretion.

USE IN SPECIFIC POPULATIONS

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus by your doctor.

• Nursing Mothers

Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug by your doctor, taking into account the importance of the drug to the mother.

v  Pediatric Use

The safety and effectiveness of levetiracetamin the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established. The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and Administration].

v  Geriatric Use

Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

v  Renal Impairment

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see Dosage and Administration].

OVERDOSAGE

• Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

Cases of drowsiness, somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma were observed with levetiracetam overdoses.

·         Management of Overdose

There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status.

·         Hemodialysis

Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.

HOW SUPPLIED/STORAGE AND HANDLING

ARO–CETAM active substance is called levetiracetam. The other ingredients are: sodium acetate trihydrate, glacial     acetic acid, Sodium chloride, water for injection.   

ARO–CETAM (levetiracetam) 1500 mg/100 mL solution for infusion is a clear, colorless to light yellow, sterile solution. It is supplied in ready-to-use, single-use 100 mL vials, available in box of 1 vial.

ARO–CETAM 1500 mg, Each vial of 100 mL contains 0.54% Sodium Chloride.

Storage

 Keep in original package and below 30^˚C and protect from light and freezing.

References

FDA label

PDR 2019

Marketing Authorization Holder:

Darou Darman Arang

Tehran-Iran

Email:info@arangpharm.com

Web site: www.arangpharm.com