Go Content Directory Georgia

Sunday, 23 September 2012

Nicotine

Class: Autonomic Drugs, Miscellaneous
VA Class: AD900
Chemical Name: S-3-(1-Methyl-2-pyrrolidinyl)pyridine
Molecular Formula: C₁₀H₁₄N₂• x(C₁₀H₁₀•C₄H₆O₂)x
CAS Number: 54-11-5
Brands: Nicotrol NS, Nicotrol Inhaler, Nicoderm CQ, Commit, Nicorette

Introduction

Ganglionic (nicotinic) cholinergic-receptor agonist.^a

Uses for Nicotine

Smoking Cessation

Used for nicotine replacement therapy as a temporary adjunct in the cessation of cigarette smoking either unsupervised (self-medication)¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ²⁴⁶ ²⁵⁷ or in conjunction with a behavior modification program under clinician supervision.¹ ² ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ¹¹ ²⁹ ³⁰ ³¹ ⁹⁶ ⁹⁷ ¹⁹¹ ¹⁹² ¹⁹³ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ²⁴⁴ ²⁴⁵ ²⁵⁷ ²⁵⁸ ²⁶³

Nicotine replacement therapy considered first-line therapy by USPHS for treatment for dependence on tobacco.²⁵⁷

Provides alternative sources of nicotine that help reduce the withdrawal symptoms associated with nicotine dependence.¹ ² ⁵⁰ ⁷⁸ ⁷⁹ ⁸⁰ ⁹⁷ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ Chewing the resin complex-containing gum may act as a substitute oral activity in behavior modification.⁵

Ulcerative Colitis

Transdermal nicotine has been used in the management of ulcerative colitis†.¹²⁵ ²⁰⁴ ²⁰⁵ ²⁰⁶ ²⁰⁷ ²⁰⁸ ²⁰⁹ ²¹⁰

Nicotine Dosage and Administration

General

To increase smoking cessation rate,¹⁰¹ ¹⁴⁴ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ use as part of a comprehensive program of multiple treatment strategies, including behavioral modification.⁴³ ⁴⁴ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹¹⁵ ¹¹⁶ ¹¹⁹ ¹²⁶ ¹³¹ ¹⁴⁴ ¹⁴⁸ ¹⁴⁹ ¹⁶⁷ ¹⁹³ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ²⁵⁷ ²⁵⁸ ^a

Individualize duration of therapy based on patient response and degree of nicotine dependence.¹ ¹⁹⁰ ²⁵⁷ ²⁶³ ²⁶⁴ ^a

Stop smoking prior to initiating nicotine replacement therapy;¹ ¹⁹⁰ ²⁵⁷ ²⁶³ ²⁶⁴ self-medication not recommended in patients who continue to smoke, chew tobacco, or use snuff or other nicotine-containing preparations.¹⁸⁸ ¹⁸⁹ ¹⁹⁰

Discontinue therapy in patients who continue to smoke 4 weeks after initiating treatment;¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ may use nicotine replacement therapy again in subsequent attempts to quit smoking.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²¹

Administration

Administer nicotine percutaneously by topical application of a transdermal system.^b ⁱ

Administer nicotine transmucosally by oral inhalation using a special nicotine oral inhaler or intranasally using a metered-dose spray pump. ^d ²⁶⁵ ^g

Administer nicotine polacrilex intrabuccally (transmucosally) as a lozenge or chewing gum.^c ^h

May be administered as a single nicotine preparation (i.e., intrabuccally, intranasally, percutaneously, or by oral inhalation); however, if single therapy does not enable patients to quit smoking, use of transdermal nicotine may be combined with another form of nicotine replacement (i.e., either buccal nicotine polacrilex or nicotine nasal spray).²⁵⁷

Buccal Administration

Chewing Gum

Self-administer one piece of gum in response to the urge to smoke.¹

Chew gum very slowly until a distinctive peppery taste of nicotine, minty, cinnamon, or orange taste of the gum, or a slight tingling in the mouth is perceived (typically about 15 chews);¹ stop chewing gum and park between cheek and gum; once tingling is almost gone (about 1 minute), repeat chewing procedure.¹ ²⁵⁷ Continue for about 30 minutes or until taste dissipates.¹ ²⁵⁷ Do not swallow gum.¹

Do not eat or drink anything other than water for 15 minutes before and during chewing of gum.¹ ¹⁹⁰ ²⁵⁷

Do not chew multiple pieces of gum simultaneously; do not chew too rapidly or chew pieces in succession.¹ May cause excessive release of nicotine and result in adverse effects (e.g., lightheadedness, nausea, vomiting, irritation of the throat and mouth, hiccups, indigestion).¹

Chew at least 9 pieces of gum daily to improve chances of quitting.^c

Do not attempt to discontinue nicotine polacrilex gum therapy until craving is satisfied by 1 or 2 pieces of the gum daily; but do not continue therapy for >6 months,¹ unless otherwise instructed by clinician.⁹ ⁴³ ⁶⁵

4-mg strength gum recommended in highly dependent smokers because of evidence of increased efficacy.^a

Lozenges

Suck on lozenge until dissolved; do not swallow, bite, or chew.²⁶⁰ ²⁶³ ²⁶⁴ Allow to dissolve slowly in the mouth over 20–30 minutes, periodically moving the lozenge (e.g., with the tongue) from one side of the mouth to the other; minimize swallowing.²⁶³ ²⁶⁴ A warm or tingling sensation may be perceived.^h

Do not eat or drink anything other than water for 15 minutes before and during sucking on the lozenge.²⁵⁷ ²⁶³ ²⁶⁴

Use at least 9 lozenges daily for the first 6 weeks to improve chances of quitting.^h

Using >1 lozenge simultaneously or using one lozenge after another in uninterrupted sequence may result in adverse effects (e.g., hiccups, heartburn, nausea).^h

Self-administer lozenge in response to nicotine craving; decrease frequency of administration over time.²⁶³ ²⁶⁴

Topical Administration

Administer percutaneously by topical application of a transdermal system once daily.^b ⁱ

Apply at the same time each day, usually after awakening.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁹ ¹⁶⁷ ¹⁸⁸ ¹⁸⁹ ²⁵⁷

Expose the adhesive surface of the system by peeling and discarding the protective liner just prior to application and apply system immediately to avoid loss of nicotine through volatilization.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁹

Apply transdermal system to a clean, dry, hairless area of intact skin⁴³ ¹⁰¹ ¹²⁹ on the trunk or upper outer arm¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁹ ¹⁶⁷ ¹⁸⁸ ¹⁸⁹ ²⁵⁷ by firmly pressing the system with the adhesive side touching the skin.¹⁰¹ ¹²⁹ ¹⁶⁷ Press system firmly in place with heel of hand for about 10 seconds, ensuring good contact, particularly around the edges.¹⁰¹ ¹²⁹ ¹⁶⁷ ^a Do not apply to sites that are oily, damaged, or irritated;⁴³ ¹⁰¹ ¹²⁹ if necessary, hair may be clipped, but do not shave area.¹⁶⁷

System may be worn for 16 or 24 hours.^b ⁱ If cravings begin upon awakening, wear patch for 24 hours.¹⁸⁹ ^b If vivid dreams or sleep disruptions occur, wear patch for 16 hours; remove at bedtime and apply new patch upon awakening.¹⁸⁹ ²⁵⁷ ^b ⁱ

If system inadvertently comes off during the period of use, apply a new system; ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁶⁷ ^a continue current application schedule or change so that the next system is applied 24 hours later.¹²⁹

Rotate application sites to minimize potential skin irritation; allow ≥1 week before reusing a given site.¹⁰¹ ¹⁰² ¹⁰³ ¹²⁹ (See Dermatologic Effects under Cautions.)

Avoid unnecessary contact with transdermal systems.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ Avoid touching eyes after handling; wash hands with water alone as soap may enhance percutaneous absorption.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁶⁷

Intranasal Administration

Administer intranasally using a metered-dose spray pump.¹⁹¹

Prime spray pump prior to initial use by spraying into a tissue until a fine spray is seen (6–8 times); discard tissue.^d

If spray pump is not used for 24 hours, reprime pump by spraying into a tissue 1–2 times.^d

Clear nasal passages prior to administration.^d

Tilt the head back slightly;¹⁹¹ ²⁵⁷ ^d insert tip of bottle into one nostril as far as is comfortable.^d Breathe through the mouth and spray once into nostril; do not sniff, swallow or inhale through the nose while administering.¹⁹¹ ²⁵⁷ Repeat this procedure for the other nostril.^d

If nose runs, sniff gently to keep nasal spray in nose; wait 2–3 minutes before blowing nose.^d

Avoid contact with skin, eyes, and mouth; if contact occurs, rinse with plain water immediately.^d If intranasal bottle breaks, wear protective gloves, wipe with paper towels, and wash surfaces thoroughly.^d

Oral Inhalation

Administer transmucosally as an inhaled vapor by oral inhalation using a special nicotine oral inhaler that mimics smoking cigarettes.²⁴⁴ ²⁴⁵ ²⁴⁶ ²⁴⁷ ²⁴⁸

Hold the oral inhaler with two hands; separate the top and bottom pieces by pushing and turning the pieces until markings line up.^g Insert one nicotine cartridge and push the cartridge until it pops into place.^g Line up markings on the top and bottom pieces of the inhaler and push pieces together tightly; lock inhaler by turning pieces until markings do not line up.^g

Place the mouthpiece of the inhaler between lips and puff on the inhaler using rapid shallow sucking (“buccal mode”);²⁴⁴ ²⁴⁸ ²⁵⁷ alternatively, inhale slowly and deeply into back of throat (“pulmonary mode”).²⁴⁸ ^g Nicotine is vaporized and absorbed in mouth and throat.^g (See Absorption under Pharmacokinetics.) Shallow puffing method generally is preferred.²⁴⁴ ²⁴⁸ ²⁵⁰ ²⁵⁷ Deep inhalation technique requires considerable effort and does not result in substantially increased drug delivery or other benefits.²⁴⁸

Individualize orally inhaled dosage to the level of nicotine replacement required; optimum results generally achieved by frequent continuous puffing of the inhaler over 20 minutes.²⁴⁴

Nicotine is used up from cartridge after about four 5-minute sessions or one 20-minute session of active puffing.²⁵⁰

When cartridge is empty, remove top of mouthpiece; discard empty cartridge away from children and pets.^g Store with mouthpiece in locked position and cartridges in plastic case.^g Clean reusable mouthpiece regularly with soap and water.²⁴⁴

Use inhaler at temperatures >60°F; cold temperatures decrease the amount of nicotine inhaled.^g

Dosage

Chewing gum and lozenge available as nicotine polacrilex; dosage expressed in terms of nicotine.¹ ²⁶⁴

Nicotine oral inhaler cartridges labeled as containing 10 mg of nicotine deliver ≤4 mg total with repeated inhalation.²⁴⁴ ²⁴⁷ ²⁵⁰ ²⁵⁷ The amount of nicotine released depends on the volume and temperature of the air passing through the inhaler.²⁴⁴ ²⁴⁵ ²⁴⁶ ²⁴⁷ ²⁴⁸ An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases approximately 4 mg of nicotine.²⁶⁵

Metered nasal spray delivers 0.5 mg of nicotine per metered spray and about 200 sprays (i.e., 100 doses) per 100-mg container.¹⁹¹ ²⁵⁷

Adults

Smoking Cessation

Buccal (Chewing Gum)

Patients who smoke <25 cigarettes daily: Chew a 2-mg piece of gum every 2 hours during weeks 1–6; chew a 2-mg piece every 2–4 hours during weeks 7–9; and chew a 2-mg piece every 4–8 hours during weeks 10–12 of therapy.^c Alternatively, chew a 2-mg piece of gum whenever the urge to smoke occurs; do not exceed 2 pieces (4 mg) per hour.¹

Patients who smoke ≥25 cigarettes daily: Chew a 4-mg piece of gum every 2 hours during weeks 1–6; chew a 4-mg piece every 2–4 hours during weeks 7–9; and chew a 4-mg piece every 4–8 hours during weeks 10–12 of therapy.^c Alternatively, chew a 4-mg piece whenever the urge to smoke occurs; do not exceed 2 pieces (8 mg) per hour.¹

Taper dosage by chewing each piece for only 10–15 minutes and gradually reducing the number of pieces chewed, or chew each piece for longer than 30 minutes but reduce the total pieces per day, or substitute regular chewing gum for some pieces.^c

Buccal (Lozenges)

Patients who smoke first cigarette >30 minutes after waking: One 2-mg lozenge every 1–2 hours during weeks 1–6; then one 2-mg lozenge every 2–4 hours during weeks 7–9; and once 2-mg lozenge every 4–8 hours during weeks 10–12.²⁶³ ²⁶⁴ ^h

Patients who smoke first cigarette ≤30 minutes after waking: One 4-mg lozenge every 1–2 hours during weeks 1–6; then one 4-mg lozenge every 2–4 hours during weeks 7–9; and one 4-mg lozenge every 4–8 hours during weeks 10–12.²⁶³ ²⁶⁴ ^h

Do not exceed 5 lozenges in 6 hours or 20 lozenges daily.²⁶³ ²⁶⁴

Discontinue therapy if mouth problems, persistent indigestion, severe sore throat, irregular heartbeat, palpitations or symptoms suggestive of overdosage (nausea, vomiting, dizziness, diarrhea, weakness, and rapid heartbeat) develop.²⁶⁴

Transdermal

Patients who smoke ≤10 cigarettes daily: Initially, 14 mg daily for 6 weeks, then 7 mg daily for 2 weeks, then discontinue.¹⁸⁹ ^b ⁱ

Patients who smoke >10 cigarettes daily: Initially, 21 mg daily for 4–6 weeks; then 14 mg daily for 2 weeks; then 7 mg daily for 2 weeks; then discontinue therapy.¹⁸⁹ ²⁵⁷ ^b ⁱ

Intranasal

Initially, 1–2 sprays (0.5–1 mg) in each nostril per hour (1–2 mg per hour total); may increase up to a maximum of 5 sprays (5 mg) in each nostril per hour (10 mg total) or a maximum total of 80 sprays (40 mg) daily.¹⁹¹ ²⁵⁷ ^e

Initially, use at least 16 sprays (8 mg total) daily to increase chance of efficacy.¹⁹¹ ²⁵⁷ Then, individualize dosage based on nicotine dependence and occurrence of symptoms of nicotine excess.¹⁹¹

Continue treatment in successfully abstinent patients for up to 8 weeks then discontinue over 4–6 weeks.¹⁹¹

Taper dosage by using only 1 spray at a time, using the spray less frequently, keeping a tally of daily usage, trying to meet a steadily reducing usage target, skipping a dose by not medicating every hour, or setting a planned “quit date” for stopping use of the spray.¹⁹¹ Some patients may not require tapering.¹⁹¹

Oral Inhalation

Initially, 6–16 cartridges daily for up to 12 weeks, then gradually decrease daily dosage over 6–12 weeks.²⁴⁴ ²⁴⁵ ²⁴⁶ ²⁵⁷

Use ≥6 cartridges daily for the first 3–6 weeks to increase chance of efficacy.²⁴⁴ Individualize dosage based on nicotine dependence and occurrence of symptoms of nicotine excess.²⁴⁴

Taper dosage by using less frequently, keeping a tally of daily usage, trying to meet a steadily reducing usage target, or setting a planned “quit date” for stopping use of the inhaler.²⁶⁵ Some patients may not require tapering.²⁶⁵

Prescribing Limits

Adults

Smoking Cessation

Buccal (Chewing Gum)

Maximum 2 pieces of 2-mg gum per hour (i.e., maximum 24 pieces [48 mg nicotine] daily).^c Maximum 12 weeks of therapy.^c

Maximum 2 pieces of 4-mg gum per hour (i.e., maximum 24 pieces [96 mg nicotine] daily).^c Maximum 12 weeks of therapy.^c

Clinician supervised: Maximum 30 pieces of 2-mg gum daily (i.e., 60 mg nicotine) or 24 pieces of 4-mg gum daily (i.e., 96 mg nicotine).¹ ¹⁹⁰ ¹⁹⁵

Buccal (Lozenges)

Maximum 5 lozenges in 6 hours or 20 lozenges daily.^h Maximum 12 weeks of therapy.^h

Transdermal

Patients who smoke ≤10 cigarettes daily: Maximum 8 weeks of therapy.^b

Patients who smoke >10 cigarettes daily: Maximum 10 weeks of therapy.^b

Continued therapy for periods longer than usually recommended may be appropriate for certain patients to promote extended abstinence.²⁵⁷ Continuation of therapy >12 weeks not recommended by manufacturer.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴

Intranasal

Maximum 5 sprays (5 mg) in each nostril per hour (maximum 10 mg total) or a maximum total of 80 sprays (40 mg) daily.¹⁹¹ ²⁵⁷ ^e

Manufacturer states that continuing therapy >12 weeks does not improve outcome.^e Safety of continuing therapy >6 months not established.^e

Oral Inhalation

Maximum 16 cartridges daily for up to 12 weeks.²⁶⁵

Manufacturer states that safety of continuing therapy >6 months not established.²⁶⁵

Special Populations

No special population dosage recommendations at this time.^a ^b

Cautions for Nicotine

Contraindications

Known hypersensitivity to nicotine, menthol (oral inhaler), or any ingredient in the formulation.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

Nicotine polacrilex gum in patients with temporomandibular joint disease.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴ (See Oral and Dental Effects under Cautions.)

Warnings/Precautions

Warnings

Nicotine Toxicity

Risk of nicotine toxicity (e.g., nausea, hypersalivation, abdominal pain, vomiting, diarrhea, perspiration, headache, dizziness, hearing and visual disturbances, mental confusion, weakness)¹ ⁴ ³⁶ ⁹⁷ ¹⁹¹ ²⁴⁴ and addiction.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴ Sustained use of nicotine preparations is not recommended.¹ ⁸¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴ Weigh risk of nicotine replacement against hazard of continued smoking concurrent with nicotine-replacement therapy and likelihood of smoking cessation without nicotine replacement.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴

Discontinue nicotine polacrilex lozenges if symptoms suggestive of overdosage (nausea, vomiting, dizziness, diarrhea, weakness, and rapid heartbeat) occur.²⁶⁴

Fetal/Neonatal Morbidity

Animal studies indicate fetal harm; pregnant women should attempt smoking cessation with educational and behavioral interventions before considering nicotine therapy.¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁸ ¹⁹¹ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ²⁴⁴ ²⁵⁷ ²⁶⁴ ^e

Use during pregnancy only if the increased likelihood of smoking cessation justifies potential risk to the fetus and patient of nicotine replacement and possible continued smoking.¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁸ ¹⁹¹ ¹⁹⁴ ¹⁹⁵ ¹⁹⁶ ²⁴⁴ ²⁵⁷ ²⁶⁴ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^e ²⁶⁵

General Precautions

Respiratory Effects

Possible exacerbation of bronchospasm.²⁴⁴ Use oral inhaler with caution in patients with bronchospastic disease;²⁴⁴ other dosage forms may be preferable.²⁴⁴

Intranasal nicotine is not recommended in patients with severe reactive airway disease.¹⁹¹ ²⁵⁷

Nasopharyngeal Effects

Nicotine nasal spray may irritate nasal mucosa;^e use of nasal spray not recommended in patients with a history of chronic nasal disorders (e.g., allergy, rhinitis, polyps, sinusitis).¹⁹¹ ²⁵⁷

Discontinue nicotine polacrilex lozenges if severe sore throat occurs.²⁶⁴

Cardiovascular Effects

Possible increased risk of adverse cardiovascular effects;¹⁴⁴ ¹⁴⁹ ¹⁶⁴ ¹⁶⁵ ²¹¹ ²¹² ²¹³ ²¹⁴ ²¹⁵ however, causal relationship between nicotine replacement therapy and cardiac complications not established.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁴⁴ ¹⁴⁸ ¹⁴⁹ ¹⁹¹ ²⁴⁴ ²⁵⁷

Discontinue therapy if irregular heartbeat or palpitations occur.²⁶⁴ ^b ^c ^h ⁱ

Use with caution and only after careful evaluation in patients with coronary heart disease (i.e., history of MI, angina pectoris), serious cardiac arrhythmias, or vasospastic diseases (e.g., Buerger's disease, Prinzmetal's variant angina, Raynaud's phenomena).¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁴⁴ ¹⁴⁸ ¹⁴⁹ ¹⁹¹ ²⁴⁴ ²⁵⁷ Benefit of nicotine replacement therapy must outweigh risks of continued cigarette smoking.⁴³ ²⁵⁷

Self-medication not recommended in patients in the immediate post-MI period, with serious arhythmias, or with severe or worsening angina.¹⁸⁸ ¹⁸⁹ ¹⁹⁰

Endocrine Effects

Possible hyperinsulinemia and insulin resistance with prolonged nicotine replacement therapy.²⁵⁴ Use with caution in hyperthyroidism, pheochromocytoma, or insulin-dependent diabetes.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

GI Effects

Possible delayed healing of peptic ulcer; use with caution.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

Discontinue nicotine polacrilex lozenges if persistent indigestion develops.²⁶⁴

Use nicotine polacrilex gum with caution in patients with a history of esophagitis.¹ ⁹⁷

Hypertension

Possible increased risk of malignant hypertension in patients with accelerated hypertension; use with caution in such patients.¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

Possible perpetuation of hypertension; use with caution in patients with systemic hypertension.^a

Nicotine Dependence

Transference of dependence on nicotine may occur;¹ ⁸¹ ⁸⁷ ⁸⁸ ⁹⁰ ⁹⁶ ⁹⁷ ⁹⁸ ¹⁹¹ ¹⁹⁵ ²⁴⁴ ²⁵⁷ potential for abuse and dependence on nicotine nasal spray appears to be greater than that for other formulations of nicotine (i.e., nicotine polacrilex gum, transdermal nicotine systems) but less than that of cigarettes.¹⁹¹ ¹⁹⁶ ²⁰¹ ²⁰² ²⁵⁷

To minimize withdrawal symptoms⁸⁷ and the risk of dependence on nicotine, withdraw gradually or discontinue use of nicotine polacrilex gum or transdermal or intranasal nicotine after 2–3 months of therapy.¹ ² ³ ³⁶ ¹⁹¹ ¹⁹⁵ ²⁴⁴

Phenylketonuria

Commit nicotine polacrilex lozenges contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 3.4 mg of phenylalanine per lozenge.²⁶⁴

Oral and Dental Effects

Risk of occlusal stress when nicotine polacrilex gum chewed for long periods of time; may result in displaced dental restorations or loosening of dental inlays or fillings.¹ ⁷² Gum may stick to dentures, dental caps, or partial bridges; if excessive sticking or damage to dental work occurs, discontinue gum and consult clinician.¹

Use nicotine polacrilex gum with caution in patients with a history of oral or pharyngeal inflammation, or dental conditions exacerbated by chewing gum.¹ ⁹⁷

Discontinue nicotine polacrilex lozenges if mouth problems develop.²⁶⁴

Dermatologic Effects

Possible skin reactions (e.g., urticaria, hives, rash) with transdermal systems.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁹ Increased risk of such reactions in patients with some dermatologic conditions (e.g., psoriasis, atopic or eczematous dermatitis).¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴

If skin reaction occurs, discontinue transdermal system and contact clinician;¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹²⁹ topical corticosteroids and/or oral antihistamines recommended.⁴³ ¹¹² ¹⁴⁴ ¹⁴⁹ ¹⁹⁵

Risk of contact sensitization with transdermal systems; serious reaction may occur with re-exposure to smoking or other nicotine products.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴

Nervous System Effects

Potential adverse nervous system effects (e.g., insomnia,¹ ¹⁰² ¹³⁶ ¹³⁷ headache,¹ ⁶⁸ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁹ ¹¹¹ ¹¹⁸ ¹³⁷ ²⁴⁴ ²⁴⁶ ²⁶³ dizziness, lightheadedness).¹ ²⁷ ¹⁰⁴ ¹⁰⁹

Specific Populations

Pregnancy

Category D.^e ²⁶⁵ (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Distributed into milk.¹ ³⁴ ⁷⁰ ⁷³ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴ ²⁵⁷ Use caution.¹ ³⁴ ⁷⁰ ⁷³ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴ ²⁵⁷

Weigh risk of exposure to nicotine in drug versus risk of nicotine and other components of tobacco smoke from cigarettes.¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

Pediatric Use

Safety and efficacy not established.¹ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ¹⁹⁶ ²⁴⁴ However, the USPHS states that nicotine replacement therapy may be considered in adolescents when there is evidence of nicotine dependence and a desire to quit the use of tobacco.¹⁹⁶ ²⁵⁷

Use or ingestion of used or unused nicotine replacement systems by children may cause poisoning or be fatal; keep used and unused containers out of reach of children.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁹¹ ²⁴⁴

Risk of choking if nicotine oral inhalers are swallowed; keep out of reach of children.²⁴⁴

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults;¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴ select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease.^e ²⁶⁵

Hepatic Impairment

Not studied in patients with hepatic impairment; use with caution.¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴

Renal Impairment

Not studied in patients with renal impairment; clearance may be decreased in patients with severe renal impairment.⁴⁴ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ²⁴⁴

Common Adverse Effects

Buccal therapy (gum): Indigestion;¹ ⁷ ²⁷ ⁸⁵ ⁹⁶ ²⁵⁷ nausea;¹ ⁶ ⁹ ²⁷ ⁶⁸ ⁸⁵ ⁹⁵ hiccups;¹ ⁷ ⁶⁸ ⁸⁹ ⁹⁴ ⁹⁶ ²⁵⁷ traumatic injury to oral mucosa and/or teeth;¹ ⁶⁸ ²⁵⁷ irritation and/or tingling of the tongue, mouth, and throat;¹ ⁵ ⁹ ²⁷ ²⁹ ⁶⁸ ⁸⁵ ⁸⁹ ⁹⁵ ⁹⁶ oral mucosal ulceration;¹ ⁵ ⁶ ⁷ ²⁹ ⁶⁸ ⁸⁹ ⁹⁶ jaw-muscle ache;¹ ⁵ ⁶ ⁷ ²⁹ ⁶⁸ eructation;¹ ⁶⁸ ⁹⁵ gum sticking to teeth;⁸⁹ unpleasant taste;⁵ ⁸⁵ ⁹⁵ dizziness;¹ ²⁷ lightheadedness;¹ ²⁷ headache;¹ ⁶⁸ insomnia.¹

Buccal therapy (lozenge): Nausea,²⁶³ dyspepsia,²⁶³ flatulence,²⁶³ headache,²⁶³ upper respiratory tract infections.²⁶³

Transdermal therapy: Application site reactions (i.e., pruritus, burning, or erythema),¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁸ ¹²⁶ ¹³⁶ ¹³⁷ ¹⁹⁵ ²⁵⁷ diarrhea,¹⁰¹ ¹⁰² dyspepsia,¹⁰³ ¹³⁷ abdominal pain,¹⁰³ dry mouth.¹⁰¹ ¹⁰² ¹⁰⁹ ¹³⁷

Intranasal therapy: Runny nose,¹⁹¹ ¹⁹⁶ ²⁰² ²⁰³ throat irritation,¹⁹¹ ¹⁹⁶ ²⁰¹ ²⁰² ²⁰³ watery eyes,¹⁹¹ ¹⁹⁶ ²⁰¹

Tuesday, 18 September 2012

Kinevac

sincalide

Dosage Form: injection, powder, lyophilized, for solution
Kinevac 5mcg

Description

Kinevac (Sincalide for Injection) is a cholecystopancreatic-gastrointestinal hormone peptide for parenteral administration. The agent is a synthetically-prepared C-terminal octapeptide of cholecystokinin. Each vial of sincalide provides a sterile nonpyrogenic lyophillized white powder consisting of 5 mcg sincalide with 170 mg mannitol, 30 mg arginine hydrochloride, 15 mg lysine hydrochloride, 9 mg potassium phosphate dibasic, 4 mg methionine, 2 mg pentetic acid, 0.04 mg sodium metabisulfite, and 0.005 mcg polysorbate 20. The pH is adjusted to 6.0 - 8.0 with hydrochloric acid and/or sodium hydroxide prior to lyophilization. Sincalide is designated chemically as L-α-aspartyl-O-sulfo-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl- L-α-aspartyl-L-phenylalaninamide. Graphic formula:

Clinical Pharmacology

When injected intravenously, sincalide produces a substantial reduction in gallbladder size by causing this organ to contract. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. The intravenous (bolus) administration of sincalide causes a prompt contraction of the gallbladder that becomes maximal in 5 to 15 minutes, as compared with the stimulus of a fatty meal which causes a progressive contraction that becomes maximal after approximately 40 minutes. Generally, a 40 percent reduction in radiographic area of the gallbladder is considered satisfactory contraction, although some patients will show area reduction of 60 to 70 percent.

Like cholecystokinin, sincalide stimulates pancreatic secretion; concurrent administration with secretin increases both the volume of pancreatic secretion and the out-put of bicarbonate and protein (enzymes) by the gland. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate. The parameters usually determined are: volume of the secretion; bicarbonate concentration; and amylase content (which parallels the content of trypsin and total protein).

Both cholecystokinin and sincalide stimulate intestinal motility, and may cause pyloric contraction which retards gastric emptying.

Indications and Usage

Kinevac (Sincalide for Injection) may be used: (1) to stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals; (2) to stimulate pancreatic secretion (especially in conjunction with secretin) prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; (3) to accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract.

Contraindications Section

The preparation is contraindicated in patients hypersensitive to sincalide and in patients with intestinal obstruction.

Warnings

Because of Kinevac’s effect on smooth muscle, pregnant patients should be advised that spontaneous abortion or premature induction of labor may occur (see Pregnancy Category B).

Precautions

General

The possibility exists that stimulation of gallbladder contraction in patients with small gallbladder stones could lead to the evacuation of the stones from the gallbladder, resulting in their lodging in the cystic duct or in the common bile duct. The risk of such an event is considered to be minimal because sincalide, when given as directed, does not ordinarily cause complete contraction of the gallbladder.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.

Teratogenic EffectsPregnancy Category B

Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed (see WARNINGS).

Labor and Delivery

Sincalide should not be administered to pregnant women near term because of its effect on smooth muscle; the possibility of inducing labor prematurely exists. The effects of sincalide on labor, delivery and lactation in animals has not been determined (see WARNINGS).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sincalide is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

Adverse Reactions

Reactions to sincalide are generally mild and of short duration. The most frequent adverse reactions were abdominal discomfort or pain, and nausea; rapid intravenous injection of 0.04 mcg sincalide per kg expectably causes transient abdominal cramping. These phenomena are usually manifestations of the physiologic action of the drug, including delayed gastric emptying and increased intestinal motility. These reactions occurred in approximately 20 percent of patients; they are not to be construed as necessarily indicating an abnormality of the billiary tract unless there is other clinical or radiologic evidence of disease.

The incidence of other adverse reactions, including vomiting, flushing, sweating, rash, hypotension, hypertension, shortness of breath, urge to defecate, headache, diarrhea, sneezing, and numbness was less than 1 percent; dizziness was reported in approximately 2 percent of patients. These manifestations are usually lessened by slower injection rate.

Overdosage

Although no overdosage reports have been received, gastrointestinal symptoms (abdominal cramps, nausea, vomiting and diarrhea) would be expected. Hypotension with dizziness or fainting might also occur. Overdosage symptoms should be treated symptomatically and should be of short duration. Starting with single bolus i.v. injection comparable to the human does of 0.4 mg/kg, sincalide caused hypotension and bradycardia in dogs. Higher doses injected once or repeatedly in dogs caused syncope and ECG changes in addition. These effects were attributed to sincalide-induced vagal stimulation in that all were prevented by pretreatment with atropine or bilateral vagotomy.

Dosage and Administration

Reconstitution and Storage

Sincalide for Injection may be stored at room temperature prior to reconstitution.

To reconstitute, aseptically add 5 mL of Sterile Water for Injection USP to the vial. This solution may be kept at room temperature and should be used within 8 hours of reconstitution, after which time any unused portion should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For prompt contraction of the gallbladder, a dose of 0.02 mcg sincalide per kg (1.4 mcg/70 kg) is injected intravenously over a 30- to 60-second interval; if satisfactory contraction of the gallbladder does not occur in 15 minutes, a second dose, 0.04 mcg sincalide per kg, may be administered. To reduce the intestinal side effects (see ADVERSE REACTIONS), an intravenous infusion may be prepared at a dose of 0.12 mcg/kg in 100 mL of Sodium Chloride Injection USP and given at a rate of 2 mL per minute; alternatively, an intramuscular dose of 0.1 mcg/kg may be given. When Kinevac (Sincalide for Injection) is used in cholecystography, roentgenograms are usually taken at five-minute intervals after the injection. For visualization of the cystic duct, it may be necessary to take roentgenograms at one-minute intervals during the first five minutes after the injection.

For the Secretin-Kinevac test of pancreatic function, the patient receives a dose of 0.25 units secretin per kg by intravenous infusion over a 60-minute period. Thirty minutes after the initiation of the secretin infusion, a separate IV infusion of Kinevac at a total dose of 0.02 mcg per kg is administered over a 30-minute interval. For example, the total dose for a 70 kg patient is 1.4 mcg of sincalide; therefore, dilute 1.4 mL of reconstituted Kinevac solution to 30 mL with Sodium Chloride Injection USP and administer at a rate of 1 mL per minute.

To accelerate the transit time of a barium meal through the small bowel, administer Kinevac after the barium meal is beyond the proximal jejunum. (Sincalide, like cholecystokinin, may cause pyloric contraction.) The recommended dose is 0.04 mcg sincalide per kg (2.8 mcg/70 kg) injected intravenously over a 30- to 60- second interval; if satisfactory transit of the barium meal has not occurred in 30 minutes, a second dose of 0.04 mcg sincalide per kg may be administered. For reduction of side effects, a 30-minute IV infusion of sincalide [0.12 mcg per kg (8.4 mcg/70 kg) diluted to approximately 100 mL with Sodium Chloride Injection USP] may be administered.

Sodium Chloride Injection dilutions may be kept at room temperature and should be used within one hour of dilution.

How Supplied

Kinevac (Sincalide for Injection) is supplied in packages of 10 vials containing 5 mcg of sincalide per vial (NDC 0270-0556-15).

Storage

Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [See USP Controlled Room Temperature].

U.S. Patent 6,803,046

Sample Outer label

Kinevac
sincalide injection, powder, lyophilized, for solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	52584-556 (0270-0556)
Route of Administration	INTRAVENOUS	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Sincalide (Sincalide)	Sincalide	5 ug in 5 mL

Inactive Ingredients
Ingredient Name	Strength
Mannitol
Arginine hydrochloride
Lysine hydrochloride
Potassium phosphate, dibasic
Methionine
Pentetic acid
Sodium metabisulfite
Polysorbate 20

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	52584-556-15	1 VIAL In 1 BAG	contains a VIAL
1		5 mL In 1 VIAL	This package is contained within the BAG (52584-556-15)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017697	11/05/2010

Labeler - General Injectables & Vaccines, Inc (108250663)

Revised: 11/2010General Injectables & Vaccines, Inc

More Kinevac resources

Kinevac Side Effects (in more detail)
Kinevac Use in Pregnancy & Breastfeeding
Kinevac Support Group
0 Reviews for Kinevac - Add your own review/rating

Kinevac Concise Consumer Information (Cerner Multum)

Kinevac Advanced Consumer (Micromedex) - Includes Dosage Information

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Barium Meal Transit
Gallbladder Contraction
Pancreatic Secretion

Sunday, 16 September 2012

Mountain Sickness / Altitude Sickness Medications

Definition of Mountain Sickness / Altitude Sickness: Acute mountain sickness is an illness that can affect mountain climbers, hikers, skiers, or travelers who ascend too rapidly to high altitude (typically above 8,000 feet or 2,400 meters). This is especially for persons who normally reside at or near sea level.

Drugs associated with Mountain Sickness / Altitude Sickness

The following drugs and medications are in some way related to, or used in the treatment of Mountain Sickness / Altitude Sickness. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Drug List:

Dexacort-Phosphate-In-Turbinaire

Dexamethasone-Intensol

Dexasone-Injection

Dexasone-La-Injection

Dexpak-Tablets-Dose-Pack

Diamox

Diamox-Sequels-Sustained-Release-Capsules

Solurex-Injection

Solurex-La-Injection

Zema-Pak-10-Day

Thursday, 13 September 2012

Zonegran

Generic Name: zonisamide (Oral route)

zoe-NIS-a-mide

Commonly used brand name(s)

In the U.S.

Zonegran

Available Dosage Forms:

Capsule

Tablet

Therapeutic Class: Anticonvulsant

Chemical Class: Sulfonamide

Uses For Zonegran

Zonisamide is used together with other medicines to control partial seizures (convulsions) in the treatment of epilepsy. This medicine is an anticonvulsant that works in the brain tissue to stop seizures.

This medicine is available only with your doctor's prescription.

Before Using Zonegran

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of zonisamide in children below 16 years of age. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of zonisamide have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of zonisamide in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require an adjustment in the dose for patients receiving zonisamide.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Ketorolac

Metformin

Naproxen

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Ginkgo

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of Zonegran

Take this medicine only as directed by your doctor to help your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a medication guide and a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Zonisamide may be taken with or without food, on a full or empty stomach. Swallow the capsule whole. Do not break, crush, or chew it.

It is important that you drink extra water every day while you take zonisamide to help prevent kidney stones.

This medicine will be used together with other seizure medicines. Keep using all of your medicines unless your doctor tells you to stop.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules):
- For seizures:
  - Adults and teenagers 16 years of age and older—At first, 100 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 400 mg per day.
  - Children and teenagers younger than 16 years of age—Use and dose must be determined by the doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Zonegran

It is very important that your doctor check your progress at regular visits to see if the medicine is working properly. Blood tests may be needed to check for unwanted effects.

It is important to tell your doctor if you become pregnant. Your doctor may want you to join a pregnancy registry for pregnant patients taking a seizure medicine.

This medicine may cause some people to become drowsy, dizzy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicines or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your medical doctor or dentist before taking any of the above while you are taking this medicine.

Contact your doctor immediately if you develop a skin rash, fever, sore throat, sores in your mouth, easy bruising, severe muscle pain or weakness, or worsening of your seizures.

Check with your doctor right away if you have sudden back pain, abdominal or stomach pain, pain while urinating, or bloody or dark urine. These may be symptoms of kidney stones.

Serious skin reactions can occur with this medicine. Stop using this medicine and check with your doctor right away if you have any of the following symptoms while taking this medicine: blistering, peeling, or loosening of the skin; chills; cough; diarrhea; itching; joint or muscle pain; red skin lesions, often with a purple center; sores, ulcers, or white spots in the mouth or on the lips; or unusual tiredness or weakness.

This medicine may make you sweat less, which causes your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking this medicine. Overheating may result in heat stroke. Also, hot baths or saunas may make you dizzy or faint while you are taking this medicine.

Do not stop taking zonisamide without first checking with your doctor. Stopping the medicine suddenly may cause your seizures to return or to occur more often. Your doctor may want you to gradually reduce the amount of medicine you are taking before stopping it completely.

This medicine may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you or your caregiver notice any of these side effects, tell your doctor right away.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines, and herbal or vitamin supplements.

Zonegran Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

Discouragement

feeling sad or empty

irritability

lack of appetite

loss of interest or pleasure

mood or mental changes

shakiness or unsteady walking

tiredness

trouble with concentrating

trouble with sleeping

Less common

Agitation

bruising

delusions

hallucinations

large, flat blue or purplish patches on the skin

rash

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Difficult or labored breathing

faintness

loss of consciousness

slow or irregular heartbeat

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Abdominal or stomach pain

anxiety

difficulty with memory

dizziness

double vision

headache

loss of appetite

nausea

restlessness

sleepiness

sleeplessness

unusual drowsiness

unusual tiredness or weakness

Less common

Aching muscles or joints

acid or sour stomach

bad, unusual, or unpleasant taste in the mouth

belching

change in taste

chills

constipation

diarrhea

difficulty with speaking

difficulty with thinking

dry mouth

fever

general ill feeling

headache

heartburn

indigestion

mental slowness

nervousness

runny or stuffy nose

sneezing

tingling, burning, or prickly feelings on the skin

uncontrolled, back and forth, or rolling eye movements

weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Zonegran side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Zonegran resources

Zonegran Side Effects (in more detail)
Zonegran Use in Pregnancy & Breastfeeding
Drug Images
Zonegran Drug Interactions
Zonegran Support Group
18 Reviews for Zonegran - Add your own review/rating

Zonegran Prescribing Information (FDA)

Zonegran Consumer Overview

Zonegran Monograph (AHFS DI)

Zonegran MedFacts Consumer Leaflet (Wolters Kluwer)

Zonisamide Professional Patient Advice (Wolters Kluwer)

Compare Zonegran with other medications

Benign Essential Tremor
Migraine Prevention
Parkinsonian Tremor
Seizures

Wednesday, 12 September 2012

Simvador 20mg

1. Name Of The Medicinal Product

Simvastatin 20mg Tablets

Simvador 20mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 20 mg of simvastatin.

Excipients: Lactose monohydrate

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-Coated Tablet

Simvastatin 20 mg tablets, are tan coloured, oval shaped, biconvex, film-coated tablets, debossed with '20' on one side and breakline on the other side, containing Simvastatin 20 mg.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening.

Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is Simvastatin 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either> 2 hours before or> 4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone orverapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. In patients taking diltiazem or amtopidine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40mg/day (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of simvastatin in pre-pubertal children is limited.

4.3 Contraindications

Hypersensitivity to simvastatin or to any of the excipients

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6)

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Simvastatin 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age

- Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), as well as gemfibrozil, ciclosporin and danazol (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlopidine with simvastatin 80 mg (see sections 4.2 and 4.5).

The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid

Physicians contemplating combined therapy with simvastatin and lipid

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastain treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to> 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods> 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone. The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting agents	Prescribing recommendations
Potent CYP3A4 inhibitors: Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone	Contraindicated with simvastatin
Gemfibrozil	Avoid but if necessary, do not exceed 10 mg simvastatin daily
Ciclosporin Danazol Other fibrates (except fenofibrate)	Do not exceed 10 mg simvastatin daily
Amiodarone Verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem Amlopidine	Do not exceed 40 mg simvastatin daily
Fusidic acid	Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.
Grapefruit juice	Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.4).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin increases the AUC of simvastatin acid presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

• Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3

• Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7

• Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlopidine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co_max of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Effects of simvastatin on the pharmacokinetics of other medicinal products.

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy: Simvastatin is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.

Treatment with Simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.)

Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin should not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Simvastatin has no or negligible influence on the ability to drive and use machines.

However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Simvastatin 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simvastatin 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (

Investigations:
Rare:	increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).
Blood and lymphatic system disorders:
Rare:	anaemia
Nervous system disorders:
Rare:	headache, paresthesia, dizziness, peripheral neuropathy
Very rare:	memory impairment
Gastrointestinal disorders:
Rare:	constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis
Hepato-biliary disorders:
Rare:	hepatitis/jaundice
Very rare:	hepatic failure
Skin and subcutaneous tissue disorders:
Rare:	rash, pruritus, alopecia
Musculoskeletal, connective tissue and bone disorders:
Rare:	myopathy*, rhabdomyolysis (see section 4.4), myalgia, muscle cramps
*In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).
General disorders and administration site conditions:
Rare:	asthenia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Psychiatric disorders:

Very rare: insomnia

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitor

ATC-Code: C10A A01

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of VLDL cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Simvastatin. In addition, Simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with Simvastatin were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with Simvastatin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Simvastatin 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups Simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level> 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the betahydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin.

Concomitant food intake does not affect the absorption. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is> 95 %.

Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was exc

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Opiates include heroin, morphine, codeine, Oxycontin, Dilaudid, methadone, and others. The reaction frequently includes sweating, shaking, headache, drug craving, nausea, vomiting, abdominal cramping, diarrhea, inability to sleep, confusion, agitation, depression, anxiety, and other behavioral changes.

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