Algerika (Capsules) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

N02BF02 (Pregabalin)

Active Substance

Pregabalin (Rec.INN registered by WHO)

Dosage Forms

	Algerika	Capsules 25 mg: 14 or 56 pcs.
		Capsules 50 mg: 14 or 56 pcs.
		Capsules 75 mg: 14 or 56 pcs.
		Capsules 150 mg: 14 or 56 pcs.
		Capsules 300 mg: 14 or 56 pcs.

Dosage Form, Packaging, and Composition

Capsules No. 3, opaque, light yellow, with black print “TEVA” on the cap and “7622” on the body; capsule contents – granulated and partially compressed powder, white or almost white.

Excipients: mannitol – 43 mg, pregelatinized corn starch – 7 mg, talc – 9 mg.

Capsule shell composition 48 mg (cap – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%; body – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Capsules No. 2, opaque, light yellow, with black print “TEVA” and a radial black band on the cap and black print “7623” and a radial black band on the body; capsule contents – granulated and partially compressed powder, white or almost white.

Excipients: mannitol – 86 mg, pregelatinized corn starch – 14 mg, talc – 18 mg.

Capsule shell composition 61 mg (cap – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%; body – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Capsules No. 3, opaque, pink cap with black print “TEVA” and light yellow body with black print “7624”; capsule contents – granulated and partially compressed powder, white or almost white.

Excipients: mannitol – 10 mg, pregelatinized corn starch – 7 mg, talc – 8 mg.

Capsule shell composition 48 mg (cap – titanium dioxide – 2.1747%, iron oxide red – 0.6996%, gelatin – up to 100%; body – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Capsules No. 2, opaque, light yellow, with black print “TEVA” on the cap and “7626” on the body; capsule contents – granulated and partially compressed powder, white or almost white.

Excipients: mannitol – 20 mg, pregelatinized corn starch – 14 mg, talc – 16 mg.

Capsule shell composition 61 mg (cap – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%; body – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Capsules No. 0, opaque, pink cap with black print “TEVA” and light yellow body with black print “7621”; capsule contents – granulated and partially compressed powder, white or almost white.

Excipients: mannitol – 40 mg, pregelatinized corn starch – 28 mg, talc – 32 mg.

Capsule shell composition 96 mg (cap – titanium dioxide – 2.1747%, iron oxide red – 0.6996%, gelatin – up to 100%; body – titanium dioxide – 2.0%, iron oxide yellow – 0.1%, gelatin – up to 100%).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Composition of the ink used for printing on capsules pharmaceutical glaze (shellac solution in ethanol) – 59.42%, iron oxide black – 24.65%, butanol* – 9.75%, purified water* – 3.249%, propylene glycol – 1.3%, isopropanol* – 0.55%, ethanol* – 1.08%, aqueous ammonia* – 0.001%.
* components removed during the capsule printing process.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Antiepileptic drug. Pregabalin is an alkylated analogue of gamma-aminobutyric acid (GABA) – (S)-3(aminomethyl)-5-methylhexanoic acid – and possesses antiepileptic and anticonvulsant activity. However, despite the structural similarity of the molecules, Pregabalin does not possess activity characteristic of GABA. Pregabalin has neither direct nor indirect GABA-ergic action.

The mechanism of action of pregabalin is based on its ability to bind to the auxiliary subunit (alpha2-delta protein) of voltage-gated calcium channels in neurons (N- and P/Q-type calcium channels), resulting in a reduction of calcium transport into neuronal cells in response to an action potential.

Pregabalin is characterized by a high degree of affinity for the alpha2-delta protein located in CNS tissues. The use of pregabalin leads to a reduction in the release of pain neurotransmitters (including glutamate, norepinephrine, and substance P) into the synaptic cleft upon neuronal excitation.

As a result of such changes under the influence of pregabalin, impulse conduction is selectively suppressed. It should be noted that Pregabalin suppresses the excitability of the neuronal network only under pathological conditions.

Pharmacokinetics

The pharmacokinetics of pregabalin in the range of recommended daily doses is linear. Interindividual variability is low (less than 20%). The pharmacokinetics of pregabalin after a single dose corresponds to the pharmacokinetics of pregabalin upon repeated administration, so there is no need for regular monitoring of pregabalin concentration.

Absorption

After oral administration on an empty stomach, Pregabalin is well absorbed from the gastrointestinal tract, C_max of pregabalin in plasma is observed after 1 hour with a single dose. With repeated administration, T_max of pregabalin does not change. The bioavailability of pregabalin does not depend on the dose taken and is at least 90%. With repeated administration of pregabalin, C_ss is reached within 24-48 hours. Food intake reduces the rate and extent of pregabalin absorption.

Thus, when pregabalin is taken simultaneously with food, T_max increases by approximately 2.5 hours, and C_max of pregabalin decreases by 25-30% (compared to data obtained after taking pregabalin on an empty stomach). It should be noted that food intake does not have a clinically significant effect on the absorption of pregabalin.

Distribution

The apparent V_d of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not characterized by binding to plasma proteins.

Pregabalin penetrates well through the blood-brain barrier and placental barriers, and is also excreted in breast milk.

Metabolism

Pregabalin is practically not metabolized. A small part of pregabalin (less than 1% of the dose) is metabolized to form an N-methylated compound, which is the main metabolite and is excreted by the kidneys. No signs of racemization of the S-enantiomer of pregabalin to the R-enantiomer have been detected.

Excretion

Pregabalin is excreted mainly by the kidneys unchanged. The mean T_1/2 is 6.3 hours. Plasma clearance of pregabalin and renal clearance are directly proportional to CrCl.

Pharmacokinetics in special clinical cases

In patients with impaired renal function, the decrease in pregabalin clearance is directly proportional to the decrease in CrCl. In patients on hemodialysis, about 50% of the taken dose is removed from the plasma after 4 hours.

Impaired liver function does not have a significant effect on the pharmacokinetics of pregabalin.

In elderly patients (over 65 years), there is a tendency for a decrease in CrCl associated with age. The clearance of pregabalin decreases in accordance with CrCl, so dose adjustment is possible.

Indications

• Neuropathic pain in adults;
• Adjunctive therapy for epilepsy with partial seizures (with or without secondary generalization) in adults;
• Generalized anxiety disorder in adults;
• Fibromyalgia in adults.

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals, in a daily dose of 150 to 600 mg in 2-3 divided doses.

The capsule is recommended to be swallowed whole, without chewing or crushing, with a sufficient amount of water.

The duration of treatment and the dose of the drug Algerika are determined by the attending physician individually for each patient depending on the nature of the disease and the individual characteristics of the patient.

For neuropathic pain, the initial dose is 150 mg/day in 2-3 divided doses. Depending on the individual response to treatment and individual tolerance, after 3-7 days the dose can be increased to 300 mg/day, and if necessary, after another 7 days the dose can be increased to 600 mg/day. The maximum daily dose is 600 mg.

For adjunctive therapy for epilepsy with partial seizures (with or without secondary generalization), the initial dose is 150 mg/day in 2-3 divided doses. Depending on the individual response to treatment and individual tolerance, after 7 days the dose can be increased to 300 mg/day, and if necessary, after another 7 days the dose can be increased to 600 mg/day. The maximum daily dose is 600 mg.

For generalized anxiety disorder, the initial dose is 150 mg/day in 2-3 divided doses. Depending on the individual response to treatment and the patient’s individual tolerance, after 7 days the dose can be increased to 300 mg/day. In the absence of positive dynamics after 7 days, the dose is increased to 450 mg/day, if necessary after another 7 days – to 600 mg/day. The maximum daily dose is 600 mg.

For fibromyalgia, the initial dose is 150 mg/day in 2-3 divided doses. Depending on the individual response to treatment and individual tolerance, after 7 days the dose can be increased to 300 mg/day. In the absence of positive dynamics after 7 days, the dose is increased to 450 mg/day, and if necessary after another 7 days the dose can be increased to 600 mg/day. The maximum daily dose is 600 mg.

If it is necessary to discontinue treatment, withdrawal of the drug Algerika is recommended to be carried out gradually over a minimum of 1 week.

In patients with impaired renal function, the dose of the drug Algerika is selected individually taking into account CrCl (Table 1). CrCl is calculated using the following formula

For men CrCl (ml/min) = (body weight in kg) × (140 – age in years)/72 × plasma creatinine concentration (mg/dl)

For women CrCl (ml/min) = CrCl for men × 0.85

In patients on hemodialysis, the daily dose of pregabalin is selected taking into account renal function (see the “Pharmacokinetics” section). Immediately after each 4-hour hemodialysis session, an additional dose is applied (Table 1).

Table 1. Selection of the dose of the drug Algerika taking into account renal function

In patients with impaired liver function, dose adjustment is not required.

Elderly patients (over 65 years) may require a reduction in the dose of pregabalin due to decreased renal function (see the “Pharmacokinetics” section).

In case of a missed dose of the drug Algerika, the next dose should be taken as soon as possible, but the missed dose should not be taken if it is already time for the next dose.

Adverse Reactions

The frequency of adverse effects is classified according to WHO recommendations: very common (≥10%); common (≥1%, but <10%); uncommon (≥0.1%, but <1%); rare (≥0.01%, but < 0.1%); very rare (including isolated cases) - < 0.01%.

Infections and infestations: uncommon – nasopharyngitis.

Blood and lymphatic system disorders: rare – neutropenia, leukopenia, thrombocytopenia.

Metabolism and nutrition disorders: common – increased appetite, increased body weight; uncommon – anorexia, hypoglycemia, hyperglycemia; rare – decreased body weight.

Nervous system disorders: very common – dizziness, somnolence; common – euphoria, confusion, decreased libido, irritability, insomnia, disorientation, ataxia, attention disturbance, coordination abnormal, memory impairment, tremor, paresthesia, balance disorder, amnesia, sedated state, lethargy; uncommon – depersonalization, anorgasmia, anxiety, depression, agitation, mood swings, insomnia exacerbated, depressed mood, word-finding difficulty, hallucinations, “nightmare” dreams, increased libido, panic attacks, apathy, cognitive disorders, hypoesthesia, nystagmus, speech disorder, myoclonic seizures, reflexes decreased, dyskinesia, psychomotor hyperactivity, postural dizziness, hyperesthesia, loss of taste sensation, burning sensation on mucous membranes and skin, intentional tremor, stupor, syncope; rare – disinhibition, elevated mood, hypokinesia, parosmia, dysgraphia.

Eye disorders: common – blurred vision, diplopia; uncommon – visual disturbance, visual field defect, visual acuity reduced, eye pain, asthenopia, as well as dry eye, eye swelling, lacrimation increased; rare – photopsia, eye irritation, mydriasis, oscillopsia (subjective sensation of oscillation of viewed objects), depth perception impaired, peripheral vision loss, strabismus, visual brightness enhancement.

Ear and labyrinth disorders: common – vertigo; rare – hyperacusis.

Cardiac disorders: uncommon – flushing, skin hyperemia, blood pressure increased, hypertension, tachycardia, first-degree atrioventricular block; rare – sinus tachycardia, sinus bradycardia, sinus arrhythmia.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, dry nasal mucosa; rare – nasal congestion, epistaxis, rhinitis, snoring, throat tightness.

Gastrointestinal disorders: common – dry mouth, abdominal distension, vomiting, constipation, flatulence; uncommon – hypersalivation, gastroesophageal reflux disease, oral mucosa hypoesthesia; rare – ascites, dysphagia, pancreatitis.

Skin and subcutaneous tissue disorders: uncommon – papular rash, hyperhidrosis; rare – cold sweat, urticaria.

Renal and urinary disorders: uncommon – dysuria, urinary incontinence; rare – oliguria, renal failure.

Musculoskeletal and connective tissue disorders: uncommon – muscle twitching, joint swelling, muscle stiffness, muscle spasms, myalgia, arthralgia, back pain, pain in extremity; rare – neck muscle spasm, neck pain, rhabdomyolysis.

Reproductive system and breast disorders: common – erectile dysfunction; uncommon – sexual dysfunction, delayed ejaculation; rare – amenorrhea, breast pain, breast enlargement, dysmenorrhea, breast discharge.

General disorders and administration site conditions: common – fatigue, edema, including peripheral, feeling drunk, gait disturbance; uncommon – asthenia, falls, thirst, chest tightness, generalized edema, chills, pain; rare – hyperthermia.

Investigations: uncommon – increased ALT, increased AST, increased CPK; rare – blood creatinine increased, hypokalemia.

Adverse effects from postmarketing surveillance

The following adverse reactions have been identified during the practical use of pregabalin. Since these reports come from patients, it has not always been possible to reliably assess their frequency or establish a causal relationship with pregabalin intake.

Nervous system disorders: frequency unknown – headache, loss of consciousness, cognitive impairment.

Eye disorders: frequency unknown – vision loss.

Gastrointestinal disorders: rarely – tongue edema, nausea, diarrhea.

Skin and subcutaneous tissue disorders: rarely – facial edema, skin itching.

Allergic reactions: frequency unknown – hypersensitivity reaction, allergic reaction, angioedema, Stevens-Johnson syndrome.

Cardiovascular system disorders: frequency unknown – chronic heart failure, QT interval prolongation.

Renal and urinary disorders: frequency unknown – urinary retention.

Respiratory system disorders: frequency unknown – pulmonary edema.

Contraindications

• Childhood and adolescence under 18 years of age;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the drug components.

With caution renal impairment; concomitant use with lorazepam, ethanol, oxycodone; elderly patients (over 65 years of age); heart failure; history of drug dependence, history of encephalopathy; diabetes mellitus.

Use in Pregnancy and Lactation

There are no reliable data on the efficacy and safety of pregabalin use during pregnancy. In this regard, the use of the drug Algerika is contraindicated.

When using the drug Algerika, women of reproductive age should use effective methods of contraception.

There are no data on the excretion of pregabalin in breast milk in women. However, experimental studies have established that Pregabalin is excreted in the milk of lactating rats. Therefore, if it is necessary to use the drug during lactation, breastfeeding should be suspended.

Use in Renal Impairment

In patients with renal impairment, the dose of the drug Algerika is selected individually taking into account CC.

Pediatric Use

Contraindicated in childhood and adolescence under 18 years of age.

Geriatric Use

With caution elderly patients (over 65 years of age).

Special Precautions

In some patients with diabetes mellitus, weight gain during treatment with the drug Algerika may require dose adjustment of hypoglycemic drugs.

Cases of hypersensitivity reactions, including angioedema, have been reported during post-marketing studies. If symptoms of angioedema appear, therapy with the drug Algerika should be discontinued immediately.

During therapy with the drug Algerika, eye disorders such as decreased visual acuity, vision loss may occur, which in most cases resolve on their own both with continued treatment and after discontinuation of pregabalin.

Cases of renal failure have been reported, which were reversible after discontinuation of pregabalin therapy.

Before starting therapy, the patient should be informed about the possible development of withdrawal syndrome after discontinuation of treatment with the drug Algerika. Data on the frequency of occurrence and severity of withdrawal symptoms depending on the dose and duration of pregabalin treatment are insufficient.

During treatment with the drug Algerika or immediately after its discontinuation, grand mal type seizures and the development of status epilepticus may occur.

Treatment with the drug Algerika may be accompanied by dizziness and drowsiness, which may increase the risk of accidental injuries (falls) in elderly patients. Until patients assess the possible effects of the drug Algerika, caution should be exercised.

Data on the possibility of discontinuing other antiepileptic drugs when seizures are suppressed by the drug Algerika and the advisability of monotherapy with this drug are insufficient.

Cases of chronic heart failure have been reported in elderly patients with cardiovascular diseases during treatment of neuropathic pain with pregabalin.

When treating pain syndrome in patients with spinal cord injuries, the risk of adverse reactions from the CNS, in particular, drowsiness, increases, which may be due to interaction with other drugs, including antispasmodics.

If suicidal thoughts or attempts appear, patients or their caregivers should immediately consult a doctor.

There are reports of drug dependence on pregabalin, so the drug Algerika should be used with caution in patients with a history of dependence on any drugs.

Cases of encephalopathy have been reported with the use of pregabalin, mainly in patients with concomitant conditions that predispose to the development of encephalopathy.

If concomitant use with opioid analgesics is necessary, measures should be taken to prevent constipation and intestinal obstruction, particularly in elderly patients.

Effect on ability to drive vehicles and operate machinery

During treatment with the drug Algerika, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, due to the possible development of adverse reactions such as dizziness, drowsiness and eye disorders.

Overdose

Symptoms data on overdose are limited. Accidental use of a dose of 8 g of pregabalin during a clinical study has been reported, which was not accompanied by any noticeable clinical manifestations.

Treatment gastric lavage**, administration of activated charcoal, symptomatic therapy, hemodialysis should be applied if necessary.

Drug Interactions

Since Pregabalin is predominantly excreted unchanged by the kidneys and is only slightly metabolized in the human body (less than 1% of the administered dose is excreted by the kidneys as metabolites), does not inhibit in vitro the metabolism of other drugs and does not bind to blood proteins, it is unlikely that Pregabalin can enter into pharmacokinetic interactions with other drugs or be the object of such interaction.

No significant clinical pharmacokinetic interaction was observed with concomitant use of pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol.

Pharmacokinetic analysis showed that oral hypoglycemic agents, diuretics and insulin, as well as phenobarbital, tiagabine and topiramate do not have a clinically significant effect on the clearance of pregabalin.

Concomitant use of pregabalin and oral contraceptives (norethisterone and/or ethinyl estradiol) does not affect the steady-state pharmacokinetics of each drug.

Multiple oral administration of pregabalin and oxycodone, lorazepam or ethanol does not have a clinically significant effect on respiratory function. Pregabalin enhanced the impairment of memory and basic motor functions caused by oxycodone. Pregabalin may enhance the effects of ethanol and lorazepam.

Concomitant use with opioid analgesics may lead to impaired lower GI function, including constipation, intestinal obstruction.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed 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.