Nerventra (Capsules) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

ATC Code

N07XX10 (Laquinimod)

Active Substance

Laquinimod

Dosage Form

Nerventra

Capsules 0.6 mg: 7, 28, or 112 pcs.

Dosage Form, Packaging, and Composition

Excipients: mannitol 302.16 mg, meglumine 10 mg, sodium stearyl fumarate 3.2 mg.

Gelatin capsule composition: titanium dioxide (E 171) 2%, gelatin up to 100%.
Ink composition: shellac 59.42%, iron oxide black dye (E 172) 24.65%, butanol 9.75%, water 3.249%, propylene glycol 1.3%, ethanol 1.08%, isopropanol 0.55%, ammonia aqueous 0.001%.

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (16) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Immunomodulatory agent

Pharmacological Action

Laquinimod is an immunomodulatory drug with a protective effect on the CNS.

In experimental animal studies, Laquinimod demonstrated efficacy in various types of autoimmune encephalomyelitis and other inflammatory/autoimmune diseases.

Although the mechanism of action of laquinimod is not fully understood, several areas of its activity have been identified.

In particular, Laquinimod has a modulating effect on the immune system, crosses the blood-brain barrier and has a direct effect on CNS parenchymal cells, without having a general immunosuppressive effect. In experimental models, this was expressed in a reduction of demyelination and a decrease in the number of axons.

In the course of clinical studies with the use of laquinimod at a dose of 0.6 mg per day in the treatment of patients with relapsing-remitting multiple sclerosis, the efficacy of laquinimod was established, which was expressed in a reduction of disease activity, a decrease in atrophic processes in the brain, a reduction in the risk of disease relapses and the number of relapses confirmed by magnetic resonance imaging (MRI) with contrast enhancement of focal lesions using gadolinium, as well as a slowing of the progression of patient disability.

Pharmacokinetics

The pharmacokinetic profile of laquinimod is characterized by high bioavailability, high plasma protein binding (more than 98%), low clearance (0.09 L/h), low volume of distribution (about 10 L), and a long terminal half-life (about 80 h). The pharmacokinetics of laquinimod are linear when used in therapeutic doses from 0.05 to 0.24 mg per day. When used once daily, Laquinimod reaches steady-state concentrations within 14 days. Concentration fluctuations with once-daily use are insignificant (about 30%).

Absorption

When taken orally, the absolute bioavailability of laquinimod is about 90%. When taken on an empty stomach, absorption is rapid, and the maximum plasma concentration (C_max) is reached within 1 hour after taking laquinimod. When taken simultaneously with a high-fat, high-calorie meal, the time to reach maximum concentration (T_max) increases by 5 hours, C_max by 30%, and the area under the concentration-time curve by 10%.

Distribution

The equilibrium volume of distribution of laquinimod is dose-independent and is about 10 liters. Laquinimod reversibly binds to plasma proteins, predominantly to serum albumin. Plasma protein binding is 98%.

Metabolism

Clinical studies have established that the systemic clearance of laquinimod is low, about 0.09 L/h. Since Laquinimod does not bind to erythrocytes, its oral clearance is 0.16 L/h (plasma clearance/0.6), which corresponds to 0.2% of hepatic blood flow.

The main pathways of laquinimod metabolism are hydroxylation of the 6-, 8-quinoline, hydroxylation of aniline, and N-demethylation of the quinoline ring. Oxidation of laquinimod occurs mainly with the participation of the CYP 3A4 isoenzyme system. Metabolites, the concentration of which is less than 1% after taking laquinimod, are pharmacologically inactive.

Excretion

Laquinimod is excreted by the kidneys and bile mainly in the form of metabolites. Clinical studies have established that approximately 79% of the administered dose is excreted within 14 days by the kidneys (51%) and intestines (28%). About 3.5% of laquinimod is excreted unchanged. The half-life is about 80 hours.

Pharmacokinetics in special clinical cases

In patients with moderate renal impairment (CrCl 30-59 ml/min/1.73 m²) taking laquinimod at a dose of 0.6 mg, C_max did not differ from the values in healthy volunteers, AUC increased by 1.4 times. The pharmacokinetics of laquinimod in patients with severe renal impairment (CrCl less than 30 ml/min/1.73 m²) has not been studied, therefore the use of laquinimod in this group of patients is not recommended.

In patients with mild and moderate hepatic impairment (Child-Pugh class A and B) taking laquinimod at a dose of 0.6 mg, C_max did not differ from the values in healthy volunteers, AUC increased by 1.2 and 2.3 times, respectively.

Pharmacokinetics in patients with severe hepatic impairment (Child-Pugh class C) has not been studied, therefore the use of laquinimod in this group of patients is not recommended.

Indications

• Relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

Orally. Once a day, regardless of meals. The capsule should be taken with a sufficient amount of liquid.

If a dose is missed, it should be taken immediately and therapy should be continued according to the same schedule from the next day.

In patients with severe hepatic impairment, the use of Nerventra is not recommended. In patients with mild and moderate hepatic impairment, dose adjustment is not required. Caution should be exercised when using Nerventra in patients with mild and moderate hepatic impairment.

In patients with severe renal impairment (CrCl less than 30 ml/min/1.73 m²), the use of Nerventra is not recommended. In patients with mild and moderate renal impairment (CrCl more than 30 ml/min/1.73 m²), dose adjustment is not required. Caution should be exercised when using Nerventra in patients with mild and moderate renal impairment.

No studies on safety and efficacy have been conducted in elderly patients, therefore Nerventra should be used with caution in this group of patients.

It is not recommended to use Nerventra in pediatric patients under 18 years of age (insufficient data on safety and efficacy).

Adverse Reactions

The most frequent adverse reactions during therapy with Nerventra were headache (19.1%), back/neck pain (14.6%), abdominal pain (10.3%). Back/neck pain, as well as increased activity of liver transaminases (4.7%) were identified as safety markers.

The presented adverse reactions were identified in phase III clinical studies. The frequency of adverse reactions compared to placebo is indicated in parentheses.

The frequency of adverse reactions is classified in accordance with the recommendations of the World Health Organization: very common – at least 10%; common – at least 1%, but less than 10%; uncommon – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%; very rare (including isolated cases) – less than 0.01%.

Blood and lymphatic system disorders common – anemia.

Nervous system disorders very common – headache; common – anxiety.

Gastrointestinal disorders very common – abdominal pain; common – constipation, dental and gingival lesions, abdominal distension; uncommon – dry mouth.

Hepatobiliary disorders common – increased activity of liver transaminases (ALT, GGT, AST).

Respiratory, thoracic and mediastinal disorders common – cough; uncommon – bronchospasm.

Skin and subcutaneous tissue disorders common – skin infections.

Musculoskeletal and connective tissue disorders very common – back/neck pain; common – arthralgia; uncommon – bursitis.

Renal and urinary disorders common – urinary tract infections; uncommon – sudden urge to urinate.

Reproductive system and breast disorders common – menstrual cycle disorder, uterine bleeding.

General disorders and administration site conditions common – peripheral edema, increased fibrinogen concentration, increased serum amylase activity.

In placebo-controlled studies, back/neck pain was reported in 14.6% of patients receiving Nerventra therapy at a dose of 0.6 mg, and in 8.3% of patients receiving placebo. Severe pain was reported in 0.7% of patients receiving Nerventra and in 0.5% of patients receiving placebo.

In three cases, back pain was described as serious adverse reactions when using Nerventra. The condition of two patients improved after symptomatic therapy, the third patient required fixation therapy at the L5-S1 level. All patients continued to participate in the study.

Budd-Chiari syndrome was recorded once in a patient with a coagulation factor V mutation.

During clinical studies, increased activity of liver transaminases was observed in 9.3% of patients receiving Nerventra therapy, compared with 5.3% in the control group.

Clinically significant increase in liver enzyme activity (3 times the upper limit of normal) was observed in 4.7% of patients receiving Nerventra therapy, more often in men. In 74% of patients, liver enzyme activity decreased on its own, despite continued therapy. No concomitant increase in the concentration of total or direct bilirubin was detected, and no signs of liver failure were noted.

Despite minor deviations of hemoglobin levels from the norm, no direct dependence of a decrease in hemoglobin concentration was found in patients taking Nerventra.

Contraindications

• Hypersensitivity to laquinimod or other components of the drug;
• Severe hepatic impairment (Child-Pugh class C);
• Severe renal impairment (CrCl less than 30 ml/min/1.73 m²);
• Concomitant use with inducers of the CYP3A4 isoenzyme (carbamazepine, Efavirenz, phenobarbital, phenytoin, rifabutin, rifampicin);
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age.

With caution

• Elderly patients;
• Concomitant use with potent (itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin) or moderate (fluconazole, diltiazem, verapamil) inhibitors of the CYP3A4 isoenzyme;
• Mild and moderate hepatic impairment;
• Mild and moderate renal impairment.

Use in Pregnancy and Lactation

Nerventra is contraindicated for use during pregnancy and breastfeeding (insufficient data on safety and efficacy).

Women of childbearing potential should use reliable methods of contraception both during therapy with Nerventra and for 4 weeks after its completion.

Use in Hepatic Impairment

With caution in mild and moderate hepatic impairment. Contraindicated in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

With caution in mild and moderate renal impairment. Contraindicated in severe renal impairment (CrCl less than 30 ml/min/1.73 m²).

Pediatric Use

It is not recommended to use Nerventra in pediatric patients under 18 years of age (insufficient data on safety and efficacy).

Geriatric Use

No studies on safety and efficacy have been conducted in elderly patients, therefore Nerventra should be used with caution in this group of patients.

Special Precautions

The use of Nerventra may be accompanied by a slight, asymptomatic increase in the activity of liver transaminases (ALT, GGT, AST), which usually may occur within the first 6 months of treatment. Return to the baseline activity level usually occurs within 3 months while continuing treatment with the drug.

The use of Nerventra should be avoided in patients with severe hepatic impairment (Child-Pugh class C).

The use of Nerventra is not recommended in patients with severe renal impairment (CrCl less than 30 ml/min/1.73 m²).

Nerventra is a potent inducer of the CYP1A2 isoenzyme of the cytochrome P450 system and, when used concomitantly with drugs metabolized by the CYP1A2 isoenzyme, may lead to a noticeable decrease in their plasma concentration.

When Nerventra is used concomitantly with substrates of the CYP1A2 isoenzyme with a narrow therapeutic index, dose adjustment and careful clinical monitoring of the patient may be required at the start of Nerventra treatment or upon its discontinuation. At the start of Nerventra treatment, the dose of the CYP1A2 isoenzyme substrate may need to be increased to maintain its efficacy. Upon discontinuation of Nerventra, the dose of the CYP1A2 isoenzyme substrate may need to be reduced to prevent overdose and, as a consequence, the development of serious adverse events (see section “Drug Interactions”).

When Nerventra and potent or moderate inhibitors of the CYP3A4 isoenzyme are used concomitantly, the AUC of laquinimod may increase. Long-term (more than 1 month) concomitant use of Nerventra and potent or moderate inhibitors of the CYP3A4 isoenzyme should be avoided (see section “Drug Interactions”).

When laquinimod is used concomitantly with inducers of the CYP3A4 isoenzyme, the plasma concentration of laquinimod and its efficacy may decrease. Concomitant use of laquinimod with inducers of the CYP3A4 isoenzyme is not recommended (see section “Drug Interactions”).

Early after the start of treatment with Nerventra, an asymptomatic decrease in hemoglobin concentration may be noted, which is usually transient and does not require discontinuation of Nerventra or the use of anti-anemic therapy.

Effect on ability to drive vehicles and operate machinery

No special studies have been conducted. However, in case of adverse reactions from the CNS, caution should be exercised when performing activities requiring increased concentration and speed of psychomotor reactions.

Overdose

No cases of overdose with Nerventra were identified during clinical studies. When taking a dose 4 times higher than the recommended dose (2.4 mg per day), the safety profile remained similar to the safety profile of patients taking the recommended dose.

Treatment symptomatic therapy.

Drug Interactions

The metabolism of laquinimod occurs mainly with the participation of the CYP3A4 isoenzyme.

Interaction with inhibitors of the CYP3A4 isoenzyme

When used concomitantly with ketoconazole at a dose of 400 mg per day for 28 days in healthy volunteers, the AUC of laquinimod increased by 3.1 times without changing the C_max.

When used concomitantly with fluconazole at a dose of 200 mg per day for 21 days in healthy volunteers, the AUC of laquinimod increased by 2.5 times without changing the C_max.

When used concomitantly with cimetidine at a dose of 1600 mg per day for 21 days in healthy volunteers, the AUC and C_max did not change.

When laquinimod and potent (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin) or moderate (e.g., fluconazole, diltiazem, verapamil) inhibitors of the CYP3A4 isoenzyme are used concomitantly, the AUC of laquinimod may increase. Long-term (more than 1 month) use of such combinations should be avoided.

Interaction with inducers of the CYP3A4 isoenzyme

When used concomitantly with rifampicin at a dose of 600 mg per day for 21 days in healthy volunteers, the AUC of laquinimod decreased by 5 times without changing the C_max.

When laquinimod is used concomitantly with inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, Efavirenz, phenobarbital, phenytoin, rifabutin, rifampicin), the concentration of laquinimod and, consequently, its efficacy may decrease, therefore the use of this combination is not recommended.

Interaction with other drugs

Substrates of the CYP1A2 isoenzyme

When caffeine was used concomitantly with repeated doses of laquinimod (0.6 mg) in healthy volunteers, the AUC and C_max of caffeine decreased by 5 and 2 times, respectively. Laquinimod is a potent inducer of the CYP1A2 isoenzyme and may lead to a noticeable decrease in the plasma concentration of drugs that are metabolized by the CYP1A2 isoenzyme. When laquinimod is used concomitantly with substrates of the CYP1A2 isoenzyme with a narrow therapeutic index (e.g., ropinirole, clozapine, methadone, theophylline), it is necessary to adjust the dose of the CYP1A2 isoenzyme substrates and monitor the patient’s clinical condition at the start of laquinimod use or upon its discontinuation. At the start of laquinimod use in this combination, the dose of the CYP1A2 isoenzyme substrates must be increased in order to maintain their efficacy. Upon discontinuation of laquinimod, the dose of the CYP1A2 isoenzyme substrates should be reduced to prevent overdose, which can lead to the development of serious adverse events from the CYP1A2 isoenzyme substrates.

Substrates of the CYP3A4 isoenzyme

When repeated doses of laquinimod (0.6 mg) were used concomitantly with midazolam in healthy volunteers, an increase in the AUC of midazolam by approximately 1.5 times was observed without a change in the C_max of midazolam.

Laquinimod is a weak inhibitor of the CYP3A4 isoenzyme, which should be considered during concomitant use with drugs that have a narrow therapeutic index.

Storage Conditions

Store at a temperature not exceeding 30°C (86°F) in a place protected from light. Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.