Api Is Official In Indian Pharmacopoeia

Published Date: 02 Nov 2017

Drug X

Pharmacopoeial Status

API is official in Indian Pharmacopoeia.20

CAS No

28721-07-5 3

ATC Code

N03AF023

Structure

220px-Oxcarbazepine 220px-Orcarbazepine_3d_structure3

Chemical Name

10,11-dihydro- 10-oxo- 5H-dibenz(b,f)azepine- 5-carboxamide3

Molecular Formula

C15H12N2O2  3

Molecular Weight

252.268 g/mol3

Physicochemical Parameters

Appearance

white to faintly yellow crystalline powder19

Solubility

Soluble in acetic acid, sparingly soluble in chloform, practically insoluble in water19, 26

BCS class

II and IV 31

LOD / Water content

0.25% (NMT 0.5%) 26

Melting Point

215oC 31

Assay

(on anhydrous basis)

99.5% w/w (Between 98.0% w/w to 102% w/w) 26

Partition

co-efficient

10.7 ± 0.2 31

Impurities / Related substances

Imp A 0.1% (NMT 1.0%) 26

Imp B ND (NMT 0.1%)

Imp C 0.02% (NMT 0.1%)

Total impurities 0.21% (NMT 1.5%)

Particle size

D90: 28.59µm (NMT 35µm) 26

D50: 10µm (NMT 10µm)

Heavy metals

Less than 20 ppm 26

Sulphated Ash

0.041% (NMT 0.1% w/w) 26

Storage

Store at room temperature at 25oC in a tight container away from light and moisture. (Brief storage between 15-30oC is permitted.) Keep all medicines away from children and pets.19

Pharmacological Parameters

Therapeutic category

Anti-epileptic20

Indications

Drug X is approved for monotherapy or adjunct therapy for partial seizures in adults and as adjunct therapy for partial seizures in children ages 4–16.22

In treatment of epilepsy, Drug X has recently been found to enhance mood and reduce anxiety symptoms than other drugs employed to treat epilepsy.3

It has been reported to be effective in treating approximately half of patients with bipolar disorder and is well tolerated.3

Pharmacological class

Iminostilbenes 16

Biopharmaceutical Parameters

Absolute Bioavailability

The absolute bioavailability of Drug X is assessed from plasma data of MHD. Bioavailability is found to be 0.99, using the non-enantio selective assay corrected for the administered dose. Thus one can conclude that Drug X when given as oral formulation can be absorbed completely.23

T max

Drug X - 0.5*(n=4)

MHD - 8*(n=8) 23

Cmax (μ mol/L)

Drug X - 0.08(0.13)

MHD - 0.24(0.20) 23

T1/2

The half-life of the Drug X is about two hours, while the half-life of MHD (active metabolite) is about nine hours. Thus, MHD is mainly responsible for the pharmacological action.19

Protein binding (tissue/ plasma)

Approximately 40% of MHD is bound to serum proteins, chiefly to albumin. Binding of MHD to proteins is independent of the serum concentration of MHD within the therapeutical range. 19

Metabolism

Drug X is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Drug X. MHD is metabolized further by conjugation with glucuronic acid. Whereas the minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).19 (Refer figure 11)

Excretion

Drug X is cleared from the body mostly in the form of metabolites which are primarily excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged Drug X. Faecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine in the form of:

glucuronides of MHD (49%) or as

unchanged MHD (27%);

the inactive DHD (approximately 3%) and

conjugates of MHD and Drug X (13%) of the dose.19

Absorption site / rate

Following oral administration of Drug X tablets, it is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged Drug X, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.19

Effect of food

Food has no effect on the rate and extent of absorption of Drug X from Drug X tablets. Although not directly studied, the oral bioavailability of the Drug X suspension is unlikely to be affected under fed conditions. Hence one can conclude that, Drug X tablets and suspension can be taken with or without food.19

Pharmaceutical Parameters 31

Bulk Density

0.299 g/mL

Tapped Density

0.591 g/mL

Compressibility index

49.407%

Hausner ratio

1.9765

Angle of Repose

ÆŸ = 73.2o

Hygroscopicity

0.19%

Table 2: Drug profile

Figure 11: Metabolism of Drug X23

Mechanism of action:

Drug X limits the repetitive firing of action potentials induced by a sustained depolarization.

This effect is facilitated by a slowing of the rate of recovery of voltage-activated Na+ channels from inactivation. At therapeutic concentrations, Drug X is selective i.e. there are no effects on spontaneous activity or on responses to GABA or glutamate. The Drug X metabolite, MHD, has similar effects and may contribute to the anti-seizure efficacy of Drug X.22 Refer (figure 12)

Figure 12: Antiseizure drug–enhanced Na+ channel inactivation. Some anti-seizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, hence reducing the ability of neurons to fire at high frequencies. It should be noted, that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate (I). A, activation gate.22

34. Pharmaco-dynamics

Drug X and its active metabolite (MHD) show anticonvulsant properties in animal seizure models. Rodents were protected against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, while they abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with Drug X or MHD. 19

Uses

Drug X is used in the treatment of epilepsy (simple, absence and complex seizures) and bipolar disorder, as well as other psychiatric conditions requiring the administration of a mood stabilizer. It also can be used to control acute episodes of mania 19-23

Safety 24

Handling: No special control measures required for the normal handling of this product. Normal room ventilation is expected to be adequate for routine handling of this product.

Storage: Store at 25°C

Stability: Stable under recommended storage conditions.

Exposure controls / personal protection: Wear appropriate clothing to avoid skin contact. Wash hands and arms thoroughly after handling.

Personal Precautions: Wear protective clothing and equipment consistent with the degree of hazard.

Environmental Precautions: For large spills, take precautions to prevent entry into waterways, sewers, or surface drainage systems.

Clean-up Methods: Collect and place it in a suitable, properly labelled container for recovery or disposal.

Drug Interactions 19-22

Sr. No.

Drug

Influence of Drug X on Drug

Influence of Drug on Drug X

1.

Carbamazepine

Mean change of less than 10%

40% decrease 

2.

Phenobarbital

14% increase

25% decrease 

3.

Phenytoin

Mean change of less than 10%

30% decrease 

4.

Valproic acid

Mean change of less than 10%

18% decrease 

5.

Hormonal Contraceptives

40-50% decrease

-

6.

Calcium Antagonists

20-30% decrease

-

7.

Anti-coagulants

No change

-

Table 3: Drug interactions

Adverse Reactions 3,19, 21, 23

Drug X can cause fatigue, drowsiness, dizziness, blurred or double vision, and may cause headaches, nausea, and vomiting. There is also evidence of difficulty in concentration and mental sluggishness. It can also cause hyponatremia (2.7% of patients), hence blood sodium levels should be tested (if the patient complains of severe fatigue). Some of these side effects (such as headache) are more pronounced shortly after a dose is taken and tend to fade with the passage of time (generally 60 to 90 minutes). A craving for salty foods (such as potato chips) and increased impulsiveness have also been noted. Other side effects include stomach pain; rash; tremor; constipation, diarrhoea, decreased appetite; and dry mouth. Skin sensitivity to sunlight also may increase, and patients could experience severe sunburns as a result of sun exposure. The frequency of adverse effects rises above a daily dosage of 1200 mg. Some patients reported a sensation of incontinence without cause after taking the drug

Contraindications3, 19-23

Pregnancy Category C

There are no adequate and well-controlled clinical studies of Drug X in pregnant women; however, Drug X is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Drug X is a human teratogen. Drug X should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Drug X and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Drug X in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.

Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Drug X is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance < 30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUG. Dose adjustment for Drug X is recommended in these patients

Suicidal tendencies

 Like other antiepileptic drugs, Drug X may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.