INSTRUCTION

for medical use of the medicinal product

 

LINESSA

 

Composition:

active substance: linezolid;

1 film-coated tablet contains linezolid 600 mg;

excipients: microcrystalline cellulose; lactose monohydrate; povidone; talc; croscarmellose sodium; magnesium stearate; colloidal anhydrous silica; sodium starch glycolate (type A); hypromellose E-15; titanium dioxide E171; polyethylene glycol-6000; propylene glycol.

 

Pharmaceutical form. Film-coated tablets.

Basic physical and chemical properties: white or almost white, oblong (as caplets) film-coated tablets with a line on one side.

 

Pharmacotherapeutic group.

Antibacterial agents for systemic use.

ATC code J01X Х08.

 

Pharmacological properties.

Pharmacodynamics.

Linessa is an antibacterial agent.

When using the drug in doses of 600 mg and 1200 mg, no significant effect on the QTc interval at the maximum concentration of the drug in blood plasma and at any other time has been found.

Pharmacokinetics.

The average linezolid pharmacokinetic parameters in adults after single and multiple oral and intravenous administrations of the drug are shown in Table 1.

 

 

Table 1. The average linezolid pharmacokinetic parameters (standard deviation) in adults

Linezolid dosage	Cmax µg/ml	Cmin µg/ml	Tmax hours	AUC * µg•h/ml	t1/2 hours	CL ml/min
400 mg tablets single dose †     every 12 hours	8.1 (1.83)   11 (4.37)	---     3.08 (2.25)	1.52 (1.01)   1.12 (0.47)	55.1 (25)   73.4 (33.5)	5.2 (1.5)   4.69 (1.7)	146 (67)   110 (49)
600 mg tablets single dose     every 12 hours	12.7 (3.96)   21.2 (5.78)	---     6.15 (2.94)	1.28 (0.66)   1.03 (0.62)	91.4 (39.3)   138 (42.1)	4.26 (1.65)   5,4 (2.06)	127 (48)   80 (29)
600 mg, i.v. injection‡ single dose     every 12 hours	12.9 (1.6)   15.1 (2.52)	---     3.68 (2.36)	0.5 (0.1)   0.51 (0.03)	80.2 (33.3)   89.7 (31)	4.4 (2.4)   4.8 (1.7)	138 (39)   123 (40)
600 mg, oral suspension single dose	11 (2.76)	---	0.97 (0.88)	80.8 (35.1)	4.6 (1.71)	141 (45)

*   AUC for a single dose = AUC_0-¥; for multiple doses = AUC_0-t

^†       Data standardized to 375 mg dose

^‡    Data standardized to 625 mg dose; intravenous dose was administered by infusion, lasting 0.5 hours

C_max = maximum plasma concentration; C_min = minimum plasma concentration; T_max = time to maximum plasma concentration; AUC = area under the curve « concentration-time »; t_1/2 = half-life; CL = systemic clearance.

Absorption

Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 1 to 2 hours of dosing. Absolute bioavailability of linezolid is approximately 100%. Therefore, linezolid can be orally or intravenously administered without dose adjustment.

Linezolid can be used regardless of food intake. The time to reach maximum plasma concentration increases from 1.5 to 2.2 hours, and Cmax is reduced by about 17% when using linezolid with high-fat food. However, the total exposure estimated as per AUC_0‑¥, is similar in both cases.

Distribution

Linezolid is rapidly distributed in tissues with good perfusion. Plasma protein binding is about 31% and is not concentration dependent. Volume of distribution at steady-state averages at about 40-50 litres in healthy adults.

Linezolid concentrations have been determined in various fluids following multiple dosing. The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1 and 0.55:1, respectively.

Biotransformation

Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (A) and the hydroxyethyl glycine metabolite (B). Metabolite A is believed to be formed by an enzymatic process, whereas the formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have shown that linezolid is minimally metabolized with the possible involvement of the human cytochrome P450 system in this process. However, the metabolic ways for linezolid have not been fully studied.

Elimination

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose is found as linezolid, 40% – as metabolite B and 10% – as metabolite A. The average renal clearance of linezolid is 40 ml/min, indicating tubular reabsorption. Linezolid is not nearly found in the faeces, whereas approximately 6% of the dose is found in the faeces as metabolite B and 3% – as metabolite A.

A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and nonrenal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.

 

Clinical particulars.

Indications.

Treatment of infections caused by of anaerobic or aerobic gram-positive susceptible strains, including infections accompanied by bacteraemia, such as:

- nosocomial pneumonia;

- community acquired pneumonia;

- complicated infections of the skin and its structures, including infections due to diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes or Streptococcus agalactiae;

- uncomplicated infections of the skin and its structures caused by Staphylococcus aureus (methicillin isolates only) or Streptococcus pyogenes;

- enterococcal infections, including vancomycin resistant strains Enterococcus faecium or faecalis.

If infectious agents include gram-negative bacteria, the combination therapy is clinically indicated.

 

Contraindications.

Hypersensitivity to linezolid or any of the drug’s excipients.

Linessa should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such medicinal product.

Unless there are facilities available for close observation and monitoring of blood pressure, Linessa should not be administered to patients with the following underlying clinical conditions or on the following types of concomitant medications:

 - patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states;

- serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-НТ₁ receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

 

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). There are very limited data from drug interaction studies and on the safety of linezolid when administered to patients on concomitant medications that might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sections “Contraindications” and “Special precautions”).

Potential interactions producing elevation of blood pressure  

In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of linezolid with either pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with linezolid.

Potential serotonergic interactions

The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

During clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been reported. Therefore, while co-administration is contraindicated (see section “Contraindications”), management of patients for whom treatment with linezolid and serotonergic agents is essential, is described in the section “Precautions for use”.

Use with tyramine-rich foods

No significant vasopressor response was observed in subjects receiving both linezolid and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting excessive amounts of food and beverages with a high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).

Drugs metabolised by cytochrome P450

Linezolid is the inductor of cytochrome P450 (CYP450). In addition, linezolid does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected with linezolid.

Concomitant use of linezolid does not significantly affect the pharmacokinetics of (S) -warfarin, which is actively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are substrates of CYP2C9, can be co-administrated with linezolid without changing the dosage regimen.

CYP 3A4 inductors

Rifampicin. The co-administration of rifampicin and linezolid decreased the linezolid C_max and AUC_0-12 by 21% and 32%, respectively. The clinical significance of this interaction has not been established. The mechanism of this interaction has not been fully studied and may be related to the induction of liver enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) may cause a similar or less severe decrease in linezolid exposure.

Antibiotics

Aztreonam. The pharmacokinetics of linezolid or aztreonam is not changed with the concomitant use of these drugs.

Gentamicin. The pharmacokinetics of linezolid or gentamicin is not changed with the concomitant use of these drugs.

Antioxidants

It is not recommended to adjust the dose of linezolid when using the drug with vitamin C or vitamin E.

 

Precautions for use.

Myelosuppression

Myelosuppression (including anaemia, leukopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases with a known consequence, after the discontinuation of linezolid, the impaired haematological parameters returned to the levels observed before treatment. Elderly patients treated with linezolid may be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis. Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function; have severe renal insufficiency; receive more than 10-14 days of therapy. Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible.

If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy, in which case intensive monitoring of blood counts and appropriate management strategies should be implemented.

In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood count.

In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving linezolid for more than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who received linezolid therapy for more than 28 days.

Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of linezolid with or without treatment for their anaemia.

Antibiotic-associated diarrhoea and colitis

Cases of pseudomembranous colitis have been reported with almost all antibacterial agents, including linezolid. Thus, it is important to consider the possibility of this diagnosis in patients who develop diarrhea after administration of any antibacterial drug. If antibiotic-associated colitis is suspected or confirmed, on-going treatment with antibacterial agents, including linezolid, should be discontinued and adequate therapeutic measures should be initiated immediately.

Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of nearly all antibiotics including linezolid and may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, on-going treatment with antibacterial agents, including linezolid, should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in such conditions.

Potential interactions producing elevation of blood pressure

Unless the cases when monitoring patients for the suggested elevation of blood pressure is available, linezolid should not be administered to patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant use of such types of drugs as: direct and indirect sympathomimetics (pseudoephedrine), vasopressors (epinephrine, norepinephrine), dopaminergic agents (dopamine, dobutamine).

Lactic acidosis

Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving linezolid should receive immediate medical attention. If lactic acidosis occurs, the benefits and risks of using linezolid should be considered.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic and peripheral), may occur as a result of this inhibition; these events are more common when the drug is used longer than 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Co-administration of linezolid and serotonergic agents is contraindicated unless the co-administration of linezolid and serotonergic agents is essential.

If co-administration of linezolid and serotonergic agents is necessary, the patient should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If such signs or symptoms occur, physicians should consider discontinuing either one or both agents. After discontinuation of serotonergic agent, these symptoms may disappear.

Peripheral and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been reported in patients treated with linezolid. These reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days.

All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. If any patients are taking linezolid for longer than the recommended 28 days, their visual function should be regularly monitored.

If peripheral or optic neuropathy occurs, the continued use of linezolid should be weighed against the potential risks.

There may be an increased risk of neuropathies when linezolid is used in patients currently taking or who have recently taken antimycobacterial medications for the treatment of tuberculosis.

Convulsions

Convulsions have been reported to occur in patients when treated with linezolid. In most of these cases, a history of seizures or risk factors for seizures was reported.

Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO); however, at the doses used for antibacterial therapy, it does not exert an antidepressant effect. There are very limited data from drug interaction studies and on the safety of linezolid when administered to patients with underlying conditions and/or on concomitant medications which might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).

Use with tyramine-rich foods

Patients should be advised against consuming large amounts of tyramine rich foods.

Superinfection

The effects of linezolid therapy on normal flora have not been evaluated in clinical trials.

The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving the recommended linezolid doses experienced drug-related candidiasis during clinical trials. If superinfection occurs during therapy, appropriate measures should be taken.

Linezolid should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk (see sections “Method of administration and dosage”).

Gender

No need to adjust the dose depending on the patient's gender.

Impairment of fertility

Possible effects of linezolid on the human male reproductive system are not known.

Clinical trials

The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.

Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene. Therefore, experience in the use of linezolid in the treatment of these conditions is limited.

Drug-resistant bacteria

It is unlikely that the administration of linezolid in the absence of a diagnosed bacterial infection or for preventive measures may harm the patient or increase the risk of drug-resistant bacteria.

Since the product contains lactose, it should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

 

Pregnancy and lactation.

Pregnancy. No adequate data on the use of linezolid in pregnant women is available. Animal studies have shown reproductive toxicity. A potential risk for humans exists. Linessa should not be used during pregnancy other than the cases when the potential benefit outweighs the potential risk.

Breastfeeding. Animal data suggest that linezolid and its metabolites may excrete into breast milk. Breastfeeding should be discontinued when using Linessa.

 

Effects on ability to drive and use machines.

Patients should be warned about the potential for dizziness or symptoms of visual impairment (see sections “Precautions for use” and “Adverse reactions”) whilst receiving linezolid. Patients should be advised not to drive or operate machinery if any of these symptoms occurs.

 

Method of administration and dosage.

Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.

Indications	Dose and method of administration	The recommended duration of treatment (consecutive days)
Nosocomial pneumonia	600 mg (adults and children over 12 years of age) intravenously or orally every 12 hours	10-14
Community acquired pneumonia (including forms accompanied by bacteraemia)
Complicated infections of skin and its structures
Infection caused by vancomycin-resistant Enterococcus faecium, including infections accompanied by bacteraemia	600 mg intravenously or orally every 12 hours	14-28
Uncomplicated infections of skin and its structures	Adults: 400 mg orally every 12 hours*   Children over 12 years of age: 600 mg orally every 12 hours	10-14

 

*- The drug is used in another dosage form with the possibility of appropriate dosage

The duration of treatment depends on several factors, such as a pathogen, a location and severity of the infection, and a clinical effect as well.

The maximum dose for adults and children should not exceed 600 mg 2 times a day.

Elderly: no dose adjustment is required.

Renal impairment (creatinine clearance < 30 ml/min): linezolid pharmacokinetics is not altered in patients with any stage of renal failure; however, two major metabolites of linezolid are accumulated in patients with renal failure including increased accumulation in patients with greater severity of renal dysfunction. Regardless of kidney function, the same plasma concentrations of linezolid were achieved, so no dose adjustment is recommended for patients with renal impairment. However, given the lack of information on the clinical relevance of the major metabolites accumulation, the use of linezolid in patients with renal impairment and the potential risks of accumulation of such metabolites should be considered. Both linezolid and two metabolites are eliminated by haemodialysis. There is no information on the effect of peritoneal dialysis on linezolid pharmacokinetics. As approximately 30% of the dose is eliminated during 3-hour haemodialysis initiated 3 hours after drug administration, linezolid should be given after dialysis in patients receiving such treatment.

Hepatic impairment: clinical data on this issue are limited, so it is recommended to prescribe linezolid only when the expected benefit of treatment outweighs the potential risk.

 

Children.

The drug in this dosage form must be prescribed to children over 12 years of age.

 

Overdose.

No specific antidote is known.

No cases of overdose have been reported.

Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion. The two primary metabolites of linezolid are also removed to some extent by haemodialysis.

 

Adverse reactions.

The adverse reactions, such as headache (2.1%), diarrhea (4.2%), nausea (3.3%) and candidiasis (including oral 0.8% and vaginal 1.1%, see list below) were most commonly reported in about 22% of patients. The most commonly reported drug-related adverse events which led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment because they experienced a drug-related adverse event.

The adverse drug reactions are listed in the following frequency classification below: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Infections and infestations

Common: candidiasis (oral and vaginal candidiasis) or fungal infections.

Uncommon: vaginitis.

Not known: antibiotic associated colitis, including pseudomembranous colitis.

Blood and the lymphatic system disorders

Uncommon: eosinophilia, leukopenia, нейтропенія, thrombocytopenia.

Not known: myelosuppression, pancytopenia, anaemia, sideroblastic anaemia.

Immune system disorders

Not known: anaphylaxis.

Metabolism and nutrition disorders

Not known: lactic acidosis, hyponatraemia.

Psychiatric disorders

Uncommon: insomnia.

Nervous system disorders

Common: headache, taste perversion (metallic taste).

Uncommon: dizziness, hypaesthesia, paraesthesia.

Not known: serotonin syndrome, convulsions, peripheral neuropathy.

Eye disorders

Uncommon: blurred vision.

Not known: optic neuropathy, optic neuritis, loss of vision, changes in colour vision, changes in visual field defect.

Ear and labyrinth disorders

Uncommon: tinnitus.

Cardiac disorders

Rare: arrhythmia (tachycardia)

Vascular disorders

Uncommon: hypertension, phlebitis, thrombophlebitis.

Rare: transient ischaemic attacks.

Gastrointestinal disorders

Common: diarrhoea, nausea, vomiting.

Uncommon: localised or general abdominal pains, constipation, dry mouth, dyspepsia, gastritis, glossitis, loose stool, pancreatitis, stomatitis, tongue discolouration or disorder.

Not known: superficial tooth discolouration.

Hepatobiliary disorders

Common: abnormal liver function test; increased AST, ALT or alkaline phosphatase.

Uncommon: increased total bilirubin.

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, diaphoresis, pruritus, rash, urticaria.

Not known: bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

Renal and urinary disorders

Common: increased BUN.

Uncommon: polyuria, increased creatinine.

Rare: renal failure.

Reproductive system and breast disorders

Uncommon: vulvovaginal disorder.

General disorders and administration site conditions

Uncommon: fatigue, fever, thirst, localized pain.

Investigations

Chemistry

Common: increased LDH, creatine kinase, lipase, amylase or non-fasting glucose. Decreased total protein, albumin, sodium or calcium. Increased or decreased potassium or bicarbonate.

Uncommon: Increased sodium or calcium. Decreased non-fasting glucose. Increased or decreased chloride.

Haematology

Common: increased neutrophils or eosinophils. Decreased haemoglobin, haematocrit or red blood cell count. Increased or decreased platelet or white blood cell counts.

Uncommon: increased reticulocyte count. Decreased neutrophils.

 

Shelf life. 3 years.

 

Storage conditions. Store in place protected from light and moisture at a temperature not exceeding 25 °С. Keep out of reach of children.

 

Packaging. 5 tablets in a blister, 1 blister in a cardboard box.

 

Terms of dispensing. On prescription.

 

Manufacturer. Bafna Pharmaceuticals Ltd., India.

 

Manufacturer’s registered address.

147, Madhavaram Red Hills Road, Grantlyon, Village Vadakarai Chennai Tamil Nadu IN 600052, India.