Exista hard capsules 150 mg No. 56

Instructions for Exista hard capsules 150 mg No. 56

Composition

active ingredient: pregabalin;

1 capsule contains 75 mg or 150 mg of pregabalin;

excipients: lactose monohydrate, corn starch; talc;

capsule shell: red iron oxide (E 172), titanium dioxide (E 171), gelatin (for 75 mg capsules); titanium dioxide (E 171), gelatin (for 150 mg capsules).

Dosage form

The capsules are hard.

Main physicochemical properties:

• hard capsules 75 mg: hard gelatin capsules size 4, opaque red-brown capsule cap, opaque white body with black imprint “75 mg”, containing white or almost white powder;
• 150 mg hard capsules: size 2 hard gelatin capsules, opaque cap and body, white in color, containing white or almost white powder.

Pharmacotherapeutic group

Antiepileptic drugs, other antiepileptic drugs.

ATX code N03A X16.

Pharmacological properties

Pharmacodynamics.

The active substance is pregabalin, which is an analogue of gamma-aminobutyric acid.

[(S)-3-(aminomethyl)-5-methylhexanoic acid].

Mechanism of action

Pregabalin binds to the auxiliary subunit (a2–d protein) of voltage-gated calcium channels in the central nervous system (CNS).

Clinical efficacy and safety

Neuropathic pain

Studies have shown the drug to be effective in treating diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The drug's effectiveness in other types of neuropathic pain has not been studied.

Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks duration with twice daily dosing and in trials of up to 8 weeks duration with three times daily dosing. Overall, the safety and efficacy profiles for the twice daily and three times daily dosing regimens were similar.

In clinical studies lasting up to 12 weeks in which the drug was used to treat neuropathic pain, a reduction in peripheral and central pain was observed after the first week and was maintained throughout the treatment period.

In controlled clinical trials of peripheral neuropathic pain, 35% of patients treated with pregabalin and 18% of patients treated with placebo achieved a 50% improvement in pain scores. Among patients who did not experience somnolence, this improvement was observed in 33% of patients treated with pregabalin and 18% of patients treated with placebo. Among patients who experienced somnolence, the proportion of patients who responded to treatment was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial of central neuropathic pain, 22% of patients treated with pregabalin and 7% of patients treated with placebo had a 50% improvement in pain scores.

Epilepsy

Combination therapy: Pregabalin has been studied in 3 controlled clinical trials of 12 weeks duration with either twice daily or three times daily dosing regimens. Overall, the safety and efficacy profiles for the twice daily and three times daily dosing regimens were similar.

A decrease in the frequency of seizures was observed already in the first week.

Children and adolescents

The efficacy and safety of pregabalin as an adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n = 65) were similar to those seen in adults. Results from a 12-week placebo-controlled study in 295 paediatric patients aged 4 to 16 years and a 14-day placebo-controlled study in 175 paediatric patients aged 1 month to 4 years, conducted to evaluate the efficacy and safety of pregabalin as adjunctive therapy for the treatment of partial-onset seizures, and two 1-year open-label safety studies in 54 and 431 paediatric patients aged 3 months to 16 years, respectively, with epilepsy, indicate that adverse reactions such as pyrexia and upper respiratory tract infections were observed more frequently in children than in adult patients with epilepsy (see sections 5.2, 5.2 and 4.8).

In a 14-day placebo-controlled study, pediatric patients (aged 1 month to <4 years) were administered pregabalin 7 mg/kg/day, pregabalin 14 mg/kg/day, or placebo. The mean 24-hour seizure frequency at baseline and last visit was 4.7 and 3.8 for pregabalin 7 mg/kg/day, 5.4 and 1.4 for pregabalin 14 mg/kg/day, and 2.9 and 2.3 for placebo, respectively. Pregabalin 14 mg/kg/day significantly reduced the log-transformed seizure frequency compared with placebo (p = 0.0223); pregabalin 7 mg/kg/day showed no improvement compared with placebo.

Monotherapy (in patients with newly diagnosed disease).

Pregabalin was studied in 1 controlled clinical trial of 56 weeks duration with a twice daily dosing regimen. Pregabalin was non-inferior to lamotrigine as assessed at 6 months for the seizure-free endpoint. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder.

Pregabalin has been studied in 6 controlled trials of 4–6 weeks duration, one 8-week study in elderly patients, and one long-term relapse prevention trial with a double-blind relapse prevention phase of 6 months duration.

A reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Assessment Scale (HAM-A) was observed as early as week 1.

In controlled clinical trials (4–8 weeks duration), 52% of patients treated with pregabalin and 38% of patients treated with placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.

In controlled trials, blurred vision was more frequently observed in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and dilated fundus examination) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity deteriorated in 6.5% of patients in the pregabalin group and 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients treated with pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients treated with pregabalin and 2.1% of patients in the placebo group.

Pharmacokinetics.

The steady-state pharmacokinetics of pregabalin were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption

Pregabalin is rapidly absorbed in the fasting state and reaches peak plasma concentrations within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥ 90% and is independent of dose. Steady state is reached after 24–48 hours after multiple doses. The rate of absorption of pregabalin is reduced when taken with food, resulting in a decrease in maximum concentration (Cmax) by approximately 25–30% and a delay in time to maximum concentration (tmax) to approximately 2.5 hours. However, taking pregabalin with food had no clinically significant effect on the extent of its absorption.

Distribution

In preclinical studies, pregabalin has been shown to cross the blood-brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is excreted in the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins.

Metabolism

Pregabalin undergoes minimal metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 98% of the radioactivity was excreted in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of the drug detected in urine, accounted for 0.9% of the administered dose. In nonclinical studies, there was no racemization of the S-enantiomer of pregabalin to the R-enantiomer.

Pregabalin is eliminated from the systemic circulation unchanged, primarily by the kidneys. The mean elimination half-life of pregabalin is 6.3 hours. The plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see sections 4.2 and 4.4).

Patients with impaired renal function or patients on hemodialysis require dose adjustment (see section "Method of administration and dosage", table).

Linearity/nonlinearity

The pharmacokinetics of pregabalin are linear over the recommended dose range. The interpatient variability in the pharmacokinetics of pregabalin is low (< 20%). The pharmacokinetics of multiple doses are predictable from single-dose data. Therefore, routine monitoring of pregabalin plasma concentrations is not required.

Sex

Kidney failure

Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, the concentration of pregabalin in plasma is reduced by approximately 50%). Since the drug is excreted mainly by the kidneys, patients with renal insufficiency should reduce the dose of the drug, and after hemodialysis, an additional dose should be used (see section "Method of administration and dosage", table).

Liver failure

No specific pharmacokinetic studies have been conducted in patients with hepatic impairment. Since pregabalin is not extensively metabolized and is excreted primarily unchanged in the urine, hepatic impairment is unlikely to have a significant effect on pregabalin plasma concentrations.

Children

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) at doses of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, and 15 mg/kg/day in a pharmacokinetic and tolerability study.

Following oral administration of pregabalin to children in the fasted state, plasma tmax was generally similar across age groups and ranged from 0.5 hours to 2 hours post-dose.

Pregabalin Cmax and area under the concentration-time curve (AUC) increased linearly with increasing dose in each age group. In children weighing <30 kg, AUC was 30% lower, due to a 43% increase in weight-adjusted clearance in these patients compared to patients weighing ≥30 kg.

The terminal half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children over 7 years of age.

In a population pharmacokinetic analysis, creatinine clearance was shown to be a significant covariate for oral pregabalin clearance and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, and this relationship was similar in pediatric and adult patients.

The pharmacokinetics of pregabalin in patients under 3 months of age have not been studied (see sections 5.1, 5.2, and 4.8).

Elderly patients

Pregabalin clearance tends to decrease with age. This decrease in oral pregabalin clearance is consistent with the age-related decrease in creatinine clearance. Patients with age-related renal impairment may require a reduction in the dose of pregabalin (see Dosage and Administration, table).

Breastfeeding period

The pharmacokinetics of pregabalin administered at a dose of 150 mg every 12 hours (300 mg daily dose) were evaluated in 10 lactating women for at least 12 weeks postpartum. Breastfeeding had no or negligible effect on the pharmacokinetics of pregabalin. Pregabalin was excreted in human milk, with mean steady-state concentrations approximately 76% of the maternal plasma concentration. The estimated dose to the breastfed infant (with a mean milk intake of 150 mL/kg/day) from a woman taking pregabalin at a dose of 300 mg/day or a maximum dose of 600 mg/day is 0.31 mg/kg/day or 0.62 mg/kg/day, respectively. These estimated doses represent approximately 7% of the total maternal daily dose on a mg/kg basis.

Indication

Neuropathic pain

Exista is indicated for the treatment of neuropathic pain in adults with damage to the peripheral and central nervous system.

Epilepsy

Exista is prescribed as adjunctive therapy for partial seizures with or without secondary generalization in adults.

Generalized anxiety disorder

Exista is indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Interaction with other medicinal products and other types of interactions

Since pregabalin is excreted primarily unchanged in the urine, undergoes minimal metabolism in humans (≤ 2% of the dose is excreted in the urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and is not bound to plasma proteins, it is unlikely that pregabalin could cause or be the target of pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

Thus, in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis demonstrated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on the clearance of pregabalin.

Oral contraceptives, norethisterone and/or ethinyl estradiol

Drugs that affect the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. During post-marketing surveillance, cases of respiratory failure, coma and death have been reported in patients taking pregabalin in combination with opioids and/or other CNS depressants. Pregabalin is likely to potentiate the cognitive and gross motor impairments caused by oxycodone.

Interactions in elderly patients

No specific pharmacodynamic interaction studies have been conducted in elderly volunteers. Drug interaction studies have only been conducted in adult patients.

Application features

Patients with diabetes

In accordance with current clinical practice, some patients with diabetes mellitus who gain weight during pregabalin therapy may require dose adjustment of their antidiabetic medicinal products.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, have been reported in post-marketing experience. If symptoms of angioedema such as facial swelling, perioral swelling or upper respiratory tract swelling occur, pregabalin should be discontinued immediately.

Dizziness, drowsiness, loss of consciousness, confusion and mental disorders

Pregabalin has been associated with dizziness and somnolence, which may increase the risk of falls in elderly patients. Loss of consciousness, confusion and mental impairment have also been reported in the post-marketing setting. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Vision disorders

In controlled trials, blurred vision was more frequently observed in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials in which ophthalmological examinations were performed, the incidence of visual acuity deterioration and visual field changes was higher in patients treated with pregabalin compared to patients in the placebo group; the incidence of fundus changes was higher in patients in the placebo group (see section "Pharmacodynamics").

Post-marketing visual adverse reactions, including vision loss, blurred vision, or other changes in visual acuity, many of which were transient, have also been reported. These visual symptoms may resolve or improve after discontinuation of pregabalin.

Kidney failure

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

Withdrawal of concomitant antiepileptic drugs

There is currently insufficient data to determine whether concomitant antiepileptic drugs can be withdrawn once seizure control is achieved with the addition of pregabalin to therapy, in order to switch to pregabalin monotherapy.

Withdrawal symptoms

Some patients have experienced withdrawal symptoms after discontinuation of short-term or long-term pregabalin therapy. The following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, nervousness, depression, suicidal ideation, pain, seizures, hyperhidrosis, and dizziness, which are indicative of physical dependence. This information should be communicated to the patient before initiating therapy.

Convulsions, including status epilepticus and grand mal seizures, may occur during pregabalin therapy or shortly after its discontinuation.

Data on pregabalin withdrawal after long-term use indicate that the incidence and severity of withdrawal symptoms may be dose-dependent.

Congestive heart failure

Congestive heart failure has been reported in some patients taking pregabalin in the post-marketing setting. This reaction has been observed primarily in the treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disease. Pregabalin should be used with caution in such patients. This phenomenon may resolve upon discontinuation of pregabalin.

Suicidal thinking and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for some indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with pregabalin.

Therefore, patients should be monitored closely for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal ideation or behavior emerge.

Post-marketing reports of lower gastrointestinal events (intestinal obstruction, paralytic ileus, constipation) have been reported when pregabalin was used with medicinal products that may cause constipation, such as opioid analgesics. Precautions should be taken to prevent constipation when pregabalin is used concomitantly with opioids (especially in women and the elderly).

Concomitant use with opioid drugs

Caution is advised when prescribing pregabalin concomitantly with opioids due to the risk of CNS depression. In a study of patients taking pregabalin concomitantly with opioids, case-control and analysis showed an increased risk of opioid-related death compared with opioid use (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19-2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04-2.22]), and there was also a trend toward a greater risk at high doses of pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24-5.06]).

Misuse, abuse or addiction

Cases of misuse, abuse and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse; the patient should be monitored for signs of misuse, abuse or dependence on pregabalin (cases of addiction, exceeding the prescribed dose, drug-seeking behavior have been reported).

Respiratory depression

Severe respiratory depression has been reported with pregabalin. Patients with impaired respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants, and the elderly may be at greater risk of developing this severe adverse reaction. Such patients may require dose adjustment.

Encephalopathy

Cases of encephalopathy have been reported, occurring predominantly in patients with underlying conditions that may predispose to encephalopathy.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening or fatal, have been reported rarely in association with pregabalin treatment. Patients should be advised of the signs and symptoms and monitored closely for skin reactions when prescribing the drug. If signs and symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment should be considered (if appropriate).

Women of childbearing potential/contraception

Use of Exista during the first trimester of pregnancy may cause serious birth defects in the fetus. Pregabalin should not be used during pregnancy unless the expected benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment.

Lactose intolerance

Exista contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Treatment of neuropathic pain of central origin due to spinal cord injury

During the treatment of central neuropathic pain caused by spinal cord injury, the incidence of adverse reactions in general and of CNS adverse reactions (e.g. antispasticity drugs) required for the treatment of this condition was increased. This should be taken into account when prescribing pregabalin for this condition.

Use during pregnancy or breastfeeding

Women of childbearing potential/contraception for women and men

Since the potential risk to humans is unknown, women of childbearing potential should use effective contraception.

Pregnancy

Animal studies have shown reproductive toxicity. Pregabalin has been shown to cross the placenta in rats (see Pharmacokinetics). Pregabalin may cross the placenta in humans.

Major congenital malformations

The drug should not be used during pregnancy unless clearly necessary (use only when the expected benefit to the mother clearly outweighs the possible risk to the fetus).

Breastfeeding period

Small amounts of pregabalin have been detected in the milk of nursing women. Nursing women should be advised that breastfeeding is not recommended while taking pregabalin.

Fertility

There are no clinical data on the effect of pregabalin on female fertility.

In a clinical study to investigate the effect of pregabalin on sperm motility, healthy male volunteers were administered pregabalin at a dose of 600 mg per day. No effect on sperm motility was observed after 3 months of treatment.

In a fertility study in female rats, adverse effects on reproductive function were observed. In a fertility study in male rats, adverse effects on reproductive function and development were observed. The clinical relevance of these findings is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

Exista may have minor or moderate influence on the ability to drive and use machines. Exista may cause dizziness and drowsiness and thus affect the ability to drive and use machines. Therefore, patients should be advised to refrain from driving, operating complex machinery or other potentially hazardous activities until it is known whether this medicine affects their ability to perform such activities.

Method of administration and doses

Method of application

Take Exista regardless of food intake.

This medicine is for oral use only.

Doses

The dose range of the drug can vary within 150–600 mg per day. The daily dose should be divided into 2 or 3 doses.

Neuropathic pain

Pregabalin therapy can be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after 3-7 days, and if necessary, to a maximum dose of 600 mg per day after another 7 days.

Epilepsy

Pregabalin therapy can be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week, the dose can be increased to a maximum of 600 mg per day.

Generalized anxiety disorder

The dose, divided into 2 or 3 doses, may vary between 150 and 600 mg per day. The need for continued therapy should be reviewed periodically.

Pregabalin therapy can be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose can be increased to 450 mg per day. After another week, the dose can be increased to a maximum of 600 mg per day.

Fibromyalgia

The recommended dose for the treatment of fibromyalgia is 300 mg to 450 mg per day. Treatment should be initiated at 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients for whom 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has been conducted with a dose of 600 mg per day, there is no evidence that this dose would provide additional benefit; it was also less well tolerated. Given the dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since Exista is primarily excreted by the kidneys, the dose should be adjusted in patients with impaired renal function.

Pregabalin withdrawal

In accordance with current clinical practice, it is recommended to discontinue pregabalin therapy gradually, over a period of at least one week, regardless of the indication.

Kidney dysfunction

Pregabalin is eliminated from the systemic circulation unchanged, primarily by the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), the dose should be reduced in patients with renal impairment as indicated in the table, based on creatinine clearance (CLcr), which is determined by the formula:

Pregabalin is effectively removed from plasma by haemodialysis (50% of the drug within 4 hours). For patients on haemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an additional dose of the drug should be administered immediately after each 4-hour haemodialysis session (see table).

Pregabalin dose adjustment according to renal function

Table

* The total daily dose (mg/day) should be divided into several doses according to the dosing regimen to obtain a single dose (mg/dose).

+ An additional dose is an additional single dose.

Liver failure

No dose adjustment is necessary for patients with hepatic impairment (see Pharmacokinetics).

Elderly patients (aged 65 and over).

Elderly patients may require a reduction in the dose of pregabalin due to impaired renal function (see section "Special warnings and precautions for use").

Children.

The safety and efficacy of Exista in children under 18 years of age have not been established. Currently available information is provided in the Adverse Reactions section, as well as in the Pharmacodynamics and Pharmacokinetics sections, however, no dosage recommendations can be made in this patient population based on the data in these sections.

Overdose

After the drug was marketed, the most common adverse reactions reported in pregabalin overdose were drowsiness, confusion, agitation, and restlessness. Seizures have also been reported.

Rare cases of coma have been reported.

Treatment of pregabalin overdose consists of general supportive measures and may include hemodialysis if necessary (see section “Method of administration and dosage”, table).

Side effects

In the clinical program for pregabalin, more than 8,900 patients received it, of whom 5,600 were participants in double-blind, placebo-controlled studies. The most frequently reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in severity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% among patients taking pregabalin and 5% among patients taking placebo. The most common adverse reactions leading to discontinuation of study drug in the pregabalin group were dizziness and somnolence.

All adverse reactions that occurred more frequently than placebo and in more than one patient are listed below; these adverse reactions are listed by system organ class and frequency: 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); frequency unknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

These adverse reactions may also be associated with the course of the underlying disease and/or concomitant use of other medications.

During the treatment of neuropathic pain of central origin caused by spinal cord injury, the frequency of adverse reactions in general and the frequency of adverse reactions from the CNS, especially drowsiness, increased (see section "Special warnings and precautions for use").

Additional adverse reactions reported during post-marketing experience are listed below and are in italics.

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Uncommon: neutropenia.

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