Nicotinell Mint 1mg Lozenge

1. Name Of The Medicinal Product

Nicotinell^® Mint 1 mg compressed lozenges

2. Qualitative And Quantitative Composition

Each piece of lozenge contains:

Active substance: 1 mg nicotine (corresponding to 3.072 mg nicotine bitartrate dihydrate).

Excipient(s): aspartame (0.01 g), maltitol (0.9 g) and sodium (9.8 mg).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Compressed lozenge

White, mint flavoured, round biconvex lozenge

4. Clinical Particulars

4.1 Therapeutic Indications

Relief of nicotine withdrawal symptoms, in nicotine dependency as an aid to smoking cessation.

Patient counselling and support normally improve the success rate.

4.2 Posology And Method Of Administration

Adults and elderly

Users should stop smoking completely during treatment with Nicotinell lozenge.

Nicotinell Mint 1 mg lozenge is recommended in smokers with a low to moderate nicotine dependency.

Nicotinell Mint 1 mg lozenge is not recommended in the case of smokers with a strong or very strong nicotine dependency.

The optimal dosage form is selected according to the following table:

If an adverse event occurs with the use of the high dose form (2 mg lozenge), use of the low dose form (1 mg lozenge) should be considered.

The initial dosage should be individualised on the basis of the patients nicotine dependence. One piece of lozenge to suck when the user feels the urge to smoke.

Initially, 1 lozenge should be taken every 1-2 hours. The usual dosage is 8-12 lozenges per day. The maximum daily dose is 30 lozenges.

Directions for use:

1. One lozenge to be sucked until the taste becomes strong.

2. The lozenge should then be lodged between the gum and cheek.

3. When the taste fades, sucking of the lozenge should commence again

4. The sucking routine will be adapted individually and should be repeated until the lozenge dissolves completely (about 30 minutes)

The treatment duration is individual. Normally, treatment should continue for at least 3 months. After 3 months, the user should gradually reduce the number of lozenges. Treatment should be discontinued when the dose has been reduced to 1-2 lozenges per day. Use of nicotine medicinal products like Nicotinell Mint 1 mg lozenge beyond 6 months is generally not recommended. Some ex-smokers may need treatment with the lozenge longer to avoid returning to smoking.

Patients who have been using oral nicotine replacement therapy beyond 9 months are advised to seek additional help and information from health care professionals.

Counselling may help smokers to quit.

Concomitant use of acidic beverages such as coffee or soda may decrease the buccal absorption of nicotine. Acidic beverages should be avoided for 15 minutes prior to sucking the lozenge.

Children and adolescents (< 18 years)

Nicotinell lozenge should not be used by people under 18 years of age without recommendation from a physician. There is no experience in treating adolescents under the age of 18 with Nicotinell lozenge.

4.3 Contraindications

Hypersensitivity to nicotine or to any of the excipients

Nicotinell lozenge should not be used by non-smokers.

4.4 Special Warnings And Precautions For Use

Dependent smokers with a recent myocardial infarction, unstable or worsening angina including Prinzmetal's angina, severe cardiac arrhythmias, uncontrolled hypertensions or recent cerebrovascular accident should be encouraged to stop smoking with non-pharmacological interventions (such as counselling). If this fails, Nicotinell lozenges may be considered but as data on safety in this patient group are limited, initiation should only be under close medical supervision.

Nicotinell lozenges should be used with caution in patients with hypertension, stable angina pectoris, cerebrovascular disease, occlusive peripheral arterial disease, heart failure, diabetes mellitus, hyperthyroidism or pheochromocytoma and severe hepatic and/or renal impairment.

Patients should initially be encouraged to stop smoking with non-pharmacological interventions (such as counselling).

Swallowed nicotine may exacerbate symptoms in subjects suffering from active oesophagitis, oral and pharyngeal inflammation, gastritis or peptic ulcer.

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in small children and may prove fatal (please see Section 4.9).

Special warnings about excipients

Nicotinell lozenges contain sweeteners, including aspartame and maltitol.

Each Nicotinell Mint 1 mg lozenge contains aspartame (E951), a source of phenylalanine equivalent to 5 mg/dose and may be harmful for people with phenylketonuria.

Because Nicotinell Mint 1 mg lozenge contains maltitol (E965), a source of fructose:

- patients with rare hereditary conditions of fructose intolerance should not take this medicine,

- patients may experience a mild laxative effect.

Calorific value 2.3 kcal/g maltitol.

Nicotinell Mint 1 mg lozenge contains 9.8 mg of sodium per piece.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drug Interactions: No information is available on interactions between Nicotinell lozenge and other medicinal products.

Smoking Cessation: Smoking but not nicotine is associated with increased CYP1A2 activity. After stopping smoking there may be reduced clearance of substrates for this enzyme and increased plasma levels of some medicinal products of potential clinical importance because of their narrow therapeutic window e.g. theophylline, tacrine, olanzapine and clozapine.

The plasma concentrations of other active substances metabolised by CYP1A2 e.g. caffeine, paracetamol, phenazone, phenylbutazone, pentazocine, lidocaine, benzodiazepines, warfarin, oestrogen and vitamin B12 may also increase. However the clinical significance of this effect for these active substances is unknown.

Smoking may lead to reduced analgesic effects of propoxyphene, reduced diuretic response to furosemide (frusemide), reduced effect of propranolol on blood pressure and heart rate and reduced responder rates in ulcer healing with H2-antagonists.

Smoking and nicotine may raise the blood levels of cortisol and catecholamines, i.e. may lead to a reduced effect of nifedipine or adrenergic antagonists and to an increased effect of adrenergic agonists.

Increased subcutaneous absorption of insulin which occurs upon smoking cessation may necessitate a reduction in insulin dose.

4.6 Pregnancy And Lactation

Pregnancy

In pregnant women, complete cessation of tobacco smoking should always be recommended without nicotine replacement therapy.

Nevertheless, in the case of failure in highly dependent pregnant smokers, tobacco withdrawal via nicotine replacement therapy may be recommended. Indeed, foetal risk is probably lower than that expected with tobacco smoking, due to:

- lower maximal plasma nicotine concentration than with inhaled nicotine

- no additional exposure to polycyclic hydrocarbons and carbon monoxide

- improved chances of quitting smoking by the third trimester.

Smoking continued during the third trimester may lead to intra-uterine growth retardation or even premature birth or stillbirth, depending on the daily amount of tobacco.

Tobacco withdrawal with or without nicotine replacement therapy should not be undertaken alone but as part of a medically supervised smoking cessation program.

In the third trimester nicotine has haemodynamic effects (e.g. changes in foetal heart rate) which could affect the foetus close to delivery. Therefore, after the sixth month of pregnancy, the lozenge should only be used under medical supervision in pregnant smokers who have failed to stop smoking by the third trimester.

Lactation

Nicotine is excreted in breast milk in quantities that may affect the child even in therapeutic doses. The lozenge, like smoking itself, should therefore be avoided during breast-feeding. Should smoking withdrawal not be achieved, use of the lozenge by breast feeding smokers should only be initiated after advice from a physician. Where nicotine replacement therapy is used whilst breast-feeding, the lozenge should be taken just after breast-feeding and not during the two hours before breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence of any risks associated with driving or operating machinery when the lozenge is used following the recommended dose. Nevertheless one should take into consideration that smoking cessation can cause behavioural changes.

4.8 Undesirable Effects

Nicotinell lozenge can cause adverse reactions similar to those associated with nicotine administered by smoking. These can be attributed to the pharmacological effects of nicotine, which are dose-dependent. Non dose-dependent adverse reactions are as follows: hypersensitivity, angioneurotic oedema and anaphylactic reactions.

Most of the adverse reactions which are reported by patients occur generally during the first 3-4 weeks after initiation of therapy.

Nicotine from lozenges may sometimes cause a slight irritation of the throat and increased salivation at the start of the treatment. Excessive swallowing of nicotine which is released in the saliva may, at first, cause hiccups. Those who are prone to indigestion may suffer initially from minor degrees of dyspepsia or heartburn; slower sucking will usually overcome this problem.

Excessive consumption of lozenges by subjects who have not been in the habit of inhaling tobacco smoke, could possibly lead to nausea, faintness and headache.

Increased frequency of aphthous ulcer may occur after abstinence from smoking.

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: very common (common (uncommon (rare (very rare (<1/10,000).

Nervous system disorders:

Common: dizziness, headache

Gastrointestinal disorders:

Common: nausea, flatulence, hiccups, gastritis, dry mouth, stomatitis and oesophagitis.

Cardiac disorders:

Uncommon: Palpitations

Rare: atrial arrhythmia

Immune system disorders:

Rare: hypersensitivity, angioneurotic oedema and anaphylactic reactions.

Certain symptoms which have been reported such as dizziness, headache and insomnia may be ascribed to withdrawal symptoms in connection with smoking cessation and may be due to insufficient administration of nicotine.

Cold sores may develop in connection with smoking cessation, but any relation with the nicotine treatment is unclear.

The patient may still experience nicotine dependence after smoking cessation.

4.9 Overdose

In overdose, symptoms corresponding to heavy smoking may be seen.

The acute lethal oral dose of nicotine is about 0.5 – 0.75 mg per kg body weight, corresponding in an adult to 40 – 60 mg. Even small quantities of nicotine are dangerous in children, and may result in severe symptoms of poisoning which may prove fatal. If poisoning is suspected in a child, a doctor must be consulted immediately.

Overdose with Nicotinell Mint 1 mg lozenge may only occur if many pieces are sucked simultaneously. Nicotine toxicity after ingestion will most likely be minimised as a result of early nausea and vomiting that occur following excessive nicotine exposure.

General symptoms of nicotine poisoning include: weakness, perspiration, salivation, throat burn, nausea, vomiting, diarrhoea, abdominal pain, hearing and visual disturbances, headache, tachycardia and cardiac arrhythmia, dyspnoea, prostration, circulatory collapse, coma and terminal convulsions.

Treatment of overdose:

Treatment of overdose should be immediate as symptoms may develop rapidly. Emesis is usually spontaneous. Administration of oral activated charcoal and gastric lavage should be considered as soon as possible and within 1 hour of ingestion. Monitor vital signs and treat symptomatically.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: N07B A01

Pharmacotherapeutic group: Drugs used in nicotine dependence

Nicotine, the primary alkaloid in tobacco products and a naturally occurring autonomous substance, is a nicotine receptor agonist in the peripheral and central nervous systems and has pronounced CNS and cardiovascular effects. On consumption of tobacco products, nicotine has proven to be addictive, resulting in craving and other withdrawal symptoms when administration is stopped. This craving and these withdrawal symptoms include a strong urge to smoke, dysphoria, insomnia, irritability, frustration or anger, anxiety, concentration difficulties, agitation and increased appetite or weight gain. The lozenge replaces part of the nicotine that would have been administrated via tobacco and reduces the intensity of the withdrawal symptoms and smoking urge.

5.2 Pharmacokinetic Properties

The absorbed amount of nicotine depends on the amount released into the mouth and absorbed through the buccal mucosa.

The main part of nicotine in Nicotinell Mint 1 mg lozenge is absorbed through the buccal mucosa. A proportion, by the swallowing of nicotine-containing saliva, reaches the stomach and intestine where it is inactivated. Due to the first-pass effect in the liver, the systemic bioavailability of nicotine is low. Consequently, in the treatment with Nicotinell Mint 1 mg lozenge the high and quick systemic nicotine concentration, as seen when smoking, is rarely obtained.

Distribution volume after intravenous administration of nicotine is approximately 2-3 1/kg and the half-life is 2 hours. Nicotine is metabolised principally in the liver and the plasma clearance is approximately 1.2 l/min; nicotine also metabolises in the kidney and lungs. Nicotine crosses the blood-brain barrier.

More than 20 metabolites have been identified, all believed to be less active than nicotine. The main metabolite is cotinine which has a half-life of 15-20 hours and with approximately 10 times higher plasma concentration than nicotine. Nicotine's plasma-protein binding is less than 5%. Changes in nicotine binding from the use of concomitant medicinal products or due to altered disease state are not expected to have significant effect on nicotine kinetics. The main metabolite in urine is cotinine (15% of the dose) and trans-3-hydroxy cotinine (45% of the dose).

About 10% of the nicotine is excreted unchanged. Up to 30% may be excreted with urine in increased diuresis and the acidity under pH 5.

The peak value for the plasma concentration of Nicotinell Mint 1 mg lozenge after a single dose is approximately 4 ng per ml and the maximal concentration at steady state is approximately 10.6 ng per ml (average plasma concentration of nicotine after smoking one cigarette is 15-30 ng per ml). Peak plasma concentration is reached after about 45 minutes following sucking of a single lozenge and after about 30 minutes at steady state.

5.3 Preclinical Safety Data

Nicotine was positive in some in-vitro genotoxicity tests but there are also negative results with the same test systems. Nicotine was negative in standard in-vivo tests.

Animal experiments have shown that nicotine induces post-implantation loss and reduces the growth of foetuses.

The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maltitol (E965)

Sodium carbonate anhydrous

Sodium hydrogen carbonate

Polyacrylate dispersion 30 per cent

Xanthan gum

Colloidal anhydrous silica

Levomenthol

Peppermint oil

Aspartame (E951)

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

12, 36, 72, 96, 144 or 204 lozenges in opaque blisters consisting of aluminium foil and PVC/PE/PVDC/PE/PVC-film. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Novartis Consumer Health (UK) Ltd

Trading as Novartis Consumer Health

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

UK

8. Marketing Authorisation Number(S)

PL 00030/0146

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 20 July 1999

Date of last renewal:16 December 2008

10. Date Of Revision Of The Text

19 November 2010

LEGAL CATEGORY

GSL

Gammaplex

human immunoglobulin g

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Bio Products Laboratory

Gammaplex®

Immune Globulin Intravenous (Human)

5% Liquid

WARNING: ACUTE RENAL DYSFUNCTION and ACUTE RENAL FAILURE

• Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Gammaplex does not contain sucrose.


• For patients at risk of renal dysfunction or failure, administer Gammaplex at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).

Indications and Usage for Gammaplex

Gammaplex is an Immune Globulin Intravenous (Human), 5% Liquid indicated for the replacement therapy of primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

Gammaplex Dosage and Administration

For Intravenous Use Only

Preparation and Handling

• Gammaplex is a clear or slightly opalescent, colorless solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy or turbid, or if it contains particulate matter.


• Do not freeze, and do not use any solution that has been frozen.


• DO NOT SHAKE.


• Gammaplex should be at room temperature (up to 25°C [77°F]) at the time of administration.


• Do not use Gammaplex beyond the expiration date on the product label.


• The Gammaplex vial is for single use only. Due to the absence of anti-microbial preservatives, promptly administer Gammaplex after piercing the cap. Dispose of partially used or unused product in accordance with local requirements.


• Infuse Gammaplex using a separate infusion line.


• Do not mix Gammaplex with other intravenous medications (including normal saline) or other IGIV products.


• An infusion pump may be used to control the rate of administration.


• If large doses of Gammaplex are to be administered, several vials may be pooled using aseptic technique. Begin infusion within 2 hours after pooling.

Recommended Dose

As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.

The recommended dose of Gammaplex for patients with PI is 300 to 800 mg/kg (6 to 16 mL/kg), administered every 3 to 4 weeks. Adjust the dosage over time to achieve the desired serum trough levels and clinical responses. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.

Administration

• Hydrate the patient adequately prior to the initiation of infusion.


• Due to the absence of anti-microbial preservatives, promptly administer Gammaplex after piercing the cap.


• Infuse Gammaplex intravenously using an intravenous infusion set preferably fitted with an in-line 15-20 micron filter.

Table 1: Recommended Infusion Rates for Gammaplex

Indication	Initial infusion rate for first 15 minutes	Maintenance infusion rate (if tolerated)
PI	0.5 mg/kg/min (0.01 mL/kg/min)	Increase gradually every 15 minutes to 4 mg/kg/min (0.08 mL/kg/min)

Monitor vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.

The observation time of patients after Gammaplex administration may vary. If the patient (a) has not received Gammaplex or another IgG product, (b) is switched from an alternative IGIV product or (c) has had a long interval since the previous infusion, prolong the observation time for adverse reactions after Gammaplex infusion.

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion often allows the reaction to disappear promptly.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer Gammaplex at the minimum infusion rate practicable, and discontinue Gammaplex administration if renal function deteriorates (see Boxed Warning, Warnings and Precautions [5.2]).

Dosage Forms and Strengths

Gammaplex is a liquid solution containing 5% IgG (50 mg/mL).

Contraindications

• Gammaplex is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.


• Gammaplex is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.

Warnings and Precautions

• Weigh the potential risks and benefits of Gammaplex against those of alternative therapies in all patients for whom Gammaplex is being considered.


• Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient.

Hypersensitivity

Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue Gammaplex infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

Gammaplex contains trace amounts of IgA (<10 μg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Gammaplex is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]).

Renal Dysfunction/Failure

Acute renal dysfunction/failure, osmotic nephropathy, and death1 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering Gammaplex. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer Gammaplex at the minimum infusion rate practicable (see Dosage and Administration [2.3]).

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Gammaplex and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Gammaplex.

Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2

Thrombotic Events

Thrombotic events may occur following treatment with Gammaplex and other IGIV products.2,3 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Gammaplex at the minimum rate of infusion practicable (see Dosage and Administration [2.3]).

Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.4

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

Hemolysis

IGIV products can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis5-7. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration8, and acute hemolysis, consistent with intravascular hemolysis, has been reported.

Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Gammaplex infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

Transfusion-related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients following IGIV treatment9. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient's serum.

TRALI may be managed using oxygen therapy with adequate ventilatory support.

Transmissible Infectious Agents

Gammaplex is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Gammaplex carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to FFF on behalf of Bio Products Laboratory (800) 843-7477. Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]).

Monitoring: Laboratory Tests

• Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of Gammaplex and at appropriate intervals thereafter.


• Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.


• If signs and/or symptoms of hemolysis are present after an infusion of Gammaplex, perform appropriate laboratory testing for confirmation.


• If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum.

Interference with Laboratory Tests

• After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.

Adverse Reactions

Two serious adverse reactions, thrombosis and chest pain, were observed in a clinical study subject receiving Gammaplex.

The most common adverse reactions to Gammaplex (reported in >5% of clinical trial subjects) were headache, fatigue, nausea, pyrexia, hypertension, myalgia, pain, and vomiting.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a multicenter, open-label, non-randomized clinical study, 50 subjects with primary humoral immunodeficiency received doses of Gammaplex ranging from 279 to 799 mg/kg every 21days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months (see Clinical Studies [14.1]). Routine premedication was not allowed. Of the 703 infusions administered, 2 (4%) subjects received premedication (antipyretic, antihistamine, or antiemetic agent) prior to 2 courses of treatment, because of experience with consecutive infusion-related adverse reactions.

All 50 subjects had an adverse event at some time during the study. Twenty-four subjects (48.0%) had an adverse reaction at some time during the study that was considered product-related. More subjects with the 21-day infusion cycle had at least one adverse reaction (14 of 22 subjects, 63.6%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 35.7%). Of these 24 subjects who showed adverse reactions, only 3 subjects had adverse reactions that were considered definitely related to Gammaplex: headache, pyrexia, tachycardia, chest discomfort, and hypertension.

The most common adverse reactions observed in this clinical trial were headache (18 subjects, 36.0%), fatigue (6 subjects, 12.0%), nausea (6 subjects, 12.0%), pyrexia (6 subjects, 12.0%), hypertension (3 subjects, 6.0%), myalgia (3 subjects, 6.0%), pain (3 subjects, 6.0%), and vomiting (3 subjects, 6.0%).

Temporally associated adverse events (AEs) are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Gammaplex infusions temporally associated with one or more AEs was 24.2% (actual proportion: 21.2%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 237 (a rate of 0.34 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period.

Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Gammaplex infusion or within 72 hours after the end of an infusion, irrespective of causality.

Table 2: Adverse Events Occurring in >5% of Subjects with PI during a Gammaplex Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality

Adverse Event	Subjects (%) [n=50]	Infusions (%) [n=703]
Headache	18 (36%)	53 (7.5%)
Sinusitis	8 (16%)	9 (1.3%)
Pyrexia	7 (14%)	10 (1.4%)
Nausea	6 (12%)	7 (1.0%)
Pain	5 (10%)	5 (0.7%)
Chills	3 (6%)	5 (0.7%)
Fatigue	3 (6%)	9 (1.3%)
Hypertension	3 (6%)	4 (0.6%)
Insomnia	3 (6%)	3 (0.4%)
Nasal Congestion	3 (6%)	3 (0.4%)
Upper respiratory tract infection	3 (6%)	5 (0.7%)
Vomiting	3 (6%)	3 (0.4%)

Of the 237 temporally associated AEs reported for the 50 subjects, the investigators judged 115 to be related to the infusion of Gammaplex. The most common temporally associated AEs judged to be related to Gammaplex infusion were headache (32% of subjects), pyrexia (8% of subjects), and nausea (8% of subjects).

Five subjects (10%) experienced seven serious AEs. Two of these serious AEs were considered related to Gammaplex treatment (thrombosis and chest pain). Three other subjects withdrew from the study due to the following AEs: paresthesia, bronchospasm, and pregnancy.

Forty-seven of the 50 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (8.5%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.

During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).

Postmarketing Experience

Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post-approval use of intravenous immune globulins10:

• Infusion reactions: hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure


• Renal: Acute renal dysfunction/failure, osmotic nephropathy


• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm


• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension


• Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome


• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)


• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test


• Gastrointestinal: Hepatic dysfunction, abdominal pain


• General/Body as a Whole: pyrexia, rigors

Drug Interactions

Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella.11,12 Inform the immunizing physician of recent therapy with Gammaplex so that appropriate measures may be taken (see Patient Counseling Information [17]).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Gammaplex. It is also not known whether Gammaplex can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gammaplex should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation13, 14

Nursing Mothers

Use of Gammaplex has not been evaluated in nursing mothers.

Pediatric Use

Six (6) pediatric patients with primary humoral immunodeficiency (2 between ages of 9 and 10, and 4 between ages 12 and 16) were included within the clinical evaluation of Gammaplex. This number of pediatric patients was too small for separate evaluation from the adult patients for safety or efficacy (see Clinical Studies [14]).

Geriatric Use

Use caution when administering Gammaplex to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events (see Boxed Warning, Warnings and Precautions [5.2, 5.4]). Do not exceed recommended doses, and administer Gammaplex at the minimum infusion rate practicable.

Eight (8) patients with primary humoral immunodeficiency at or over the age of 65 were included within the clinical evaluation of Gammaplex. This number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy (see Clinical Studies [14]).

Gammaplex Description

Gammaplex is a ready to use sterile solution of polyclonal human Immunoglobulin G for IV administration that contains sorbitol, glycine and polysorbate 80 as stabilizers. Specifically, Gammaplex contains approximately 5 g normal human immunoglobulin and 5 g D-sorbitol in 100 mL of buffer solution containing: 0.6 g glycine, 0.2 g sodium acetate, 0.3 g sodium chloride, and ~5 mg polysorbate 80. Immunoglobulin G purity is > 95%, the pH is in the range of 4.8 to 5.1, and osmolality is not less than 240 mOsmol/kg (typically 420 to 500 mOsmol/kg). The distribution of the four IgG subclasses is approximately 64% IgG1, 30% IgG2, 5% IgG3, and 1% IgG4. The content of IgA is lower than 10 µg/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification. Gammaplex contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.

Gammaplex is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis.

Gammaplex is manufactured from plasma, obtained from healthy US donors, that have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma. There are several stages within this manufacturing process that contribute to viral reduction, including management of donors, screening of donations and specific virus removal steps during manufacturing.

All plasma donations are screened for antibody to HIV-1/2 and HCV, and hepatitis B surface antigen (HBsAg). Furthermore, plasma mini-pools (512 donations per pool) undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and Parvovirus B19. Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and Parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma.

There are three processing steps specifically designed to remove or inactivate viruses:

1) Solvent/Detergent treatment is targeted to enveloped viruses;

2) A virus filtration step using Pall Ultipor DV20 is designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and

3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses.

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. In addition, each step was validated to provide robust virus reduction. The table below presents the contribution of each process step to virus reduction and the overall process reduction.

Table 3: Viral Reduction by Process Step

Virus	Type (Envelope/Genome)	Size (nm)	Process Log10 Reduction of Virus (LRV) over manufacturing step			Total LRV
			Solvent Detergent	20 nm filtration	Terminal low pH/elevated temperature incubation
HIV: Human immunodeficiency virus SIN: Sindbis virus, model for hepatitis C virus (HCV) WNV: West Nile Virus BVDV: Bovine viral diarrhea virus, model for HCV IBR: Infectious bovine rhinotracheitis, bovine herpesvirus model for enveloped DNA viruses including hepatitis B HAV: Hepatitis A virus EMC: Encephalomyocarditis, model for HAV NA: Not applicable, solvent detergent step is limited to the inactivation of enveloped viruses I: Inactivation by the product intermediate precluded the accurate estimation of the removal of these viruses by the filtration step NT: Not tested B19: Viral clearance of Human Parvovirus B19 was investigated experimentally at the 20 nm filtration step. The estimated Log reduction Factor obtained was 6.0
HIV	Env/RNA	80-100	>6.8	I	>6.1	>12.9
SIN	Env/RNA	70	>6.7	6.2	>7.3	>20.2
WNV	Env/RNA	50	>6.4	I	NT	>6.4
BVDV	Env/RNA	40-60	>5.6	I	>6.1	>11.7
IBR	Env/DNA	200	>5.0	I	>6.3	>11.3
HAV	Non-Env/RNA	30	NA	>4.8	1.1	>5.9
EMC	Non-Env/RNA	30	NA	>4.8	2.7	>7.5

Gammaplex - Clinical Pharmacology

Mechanism of Action

Gammaplex is a replacement therapy for primary humoral immunodeficiency. It acts through a broad spectrum of opsonic and neutralizing IgG antibodies against pathogens and their toxins involving antigen binding and effector functions15,16. However, the mechanism of action in PI has not been fully elucidated.

Pharmacokinetics

In the clinical study assessing safety and efficacy in primary humoral immunodeficiency, the pharmacokinetics of Gammaplex was assessed for 28 days after administration to 24 subjects on 21- or 28-day infusion cycles. Blood samples for pharmacokinetic (PK) analysis were obtained after Infusion 9 for subjects on a 21-day schedule (9 subjects) and after Infusion 7 for subjects on a 28-day schedule (15 subjects), i.e., during the sixth month after initiation of Gammaplex treatment.

The mean dose (range) for those on the 21-day schedule was 476 mg/kg (range: 330 to 721 mg/kg), and it was 468 mg/kg (range: 324 to 799 mg/kg) for those on the 28-day schedule. Table 4 summarizes the PK parameters of Gammaplex, measured as serum concentrations of total IgG.

Assessment of the clinical relevance of half-life measurements in this study should be viewed with caution. Although half-life estimates are provided for total IgG and the specific antibodies, drug elimination half-lives should be measured over a minimum period of at least 3 half-lives. However, the short dosing intervals relative to the long half-life of IgG in this clinical trial do not permit accurate assessment of half-life.

Table 4: Pharmacokinetic Parameters of Gammaplex in Subjects with PI

Parameter (unit)	21-day Dosing Interval (n=9)	28-day Dosing Interval (n=15)
	Mean ± SD (Range)	Mean ± SD (Range)
tau = dosing interval
* n=14 for these calculations
Cmax (mg/mL)	21.6 ± 3.8 (16.3-27.3)	21.4 ± 4.3 (15.9-31.0)
Tmax (hr)	5.4 ± 7.2 (2.1-24.5)	6.1 ± 11.6 (2.4-48.1)
AUC0-tau (days*mg/mL)	289 ± 41 (214-365)	346 ± 52* (262-455)*
Half-Life (days)	42 ± 26 (22-108)	41 ± 14* (22-70)*
Clearance (mL/days/kg)	0.59 ± 0.24 (0.19-1.02)	0.58 ± 0.27* (0.24-1.28)*

Clinical Studies

In a Phase 3 multicenter, open-label study to evaluate the efficacy, safety, and pharmacokinetics of Gammaplex in primary humoral immunodeficiency, 50 subjects on regular IGIV replacement therapy for at least 3 months prior to participation were treated for 12 months at 21-day (22 subjects) or 28-day (28 subjects) dosing intervals. Out of the 50 subjects, 26 were male and 24 were female, and 46 were Caucasian. They were in the age range of 9 to 78 years.

Doses ranged from 279 mg/kg to 799 mg/kg. The mean dose (range) for the 21-day interval was 465 mg/kg (330 - 693 mg/kg); the mean dose (range) for the 28-day interval was 458 mg/kg (326 - 790 mg/kg). Subjects received a total of 703 infusions of Gammaplex. The maximum infusion rate allowed during this study was 0.08 mL/kg/min.

The primary analysis for efficacy was based on the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis, per subject per year17. Other important clinical analyses for efficacy were based on the annual rate of infections, antibiotic use, days out of work/school/day care or unable to perform normal activities due to illness, and days of hospitalization.

During the 12-month study period, no serious acute bacterial infections occurred in any subject with an onset date between the first infusion of Gammaplex and the first follow-up visit, inclusive. Thus, the mean event rate of serious, acute, bacterial infections per year was zero (with an upper 1-sided 99% confidence interval of 0.101).

Table 5: Summary of Efficacy Results in Subjects with PI

Number of Subjects	50
Total Number of Subject Days	16715
* Defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess. † Upper 1-sided 99% confidence interval: 0.101
Infections
Annual rate of confirmed serious acute bacterial infections*	0 /subject year †
Annual rate of other infections (median)	3.07 infections/subject year
Antibiotic use (therapeutic)
Number of subjects (%)	40 (80%)
Annual rate	47.2 days/subject year
Out of work/school/day care or unable to perform normal activities due to illness
Number of subjects (%)	23 (46%)
Number of days (%)	394 (2.36%)
Annual rate	8.73 days/subject year
Hospitalization
Number of subjects (%)	4 (8%)
Number of days (%)	29 (0.17%)
Annual rate	0.75 days/subject year

Duration of exposure in all tables relating to GMX01 was calculated as the difference between the date of the last visit (first follow-up visit) i.e. approximately 10-14 days following the last dose of Gammaplex and the date of the first Gammaplex infusion (plus one day).

REFERENCES

1. Gupta N, Ahmed I, Nissel-Horowitz S, Patel D, Mehrotra B. Intravenous gammaglobulin-associated acute renal failure. Am J Hematol 2001; 66:151-152.


2. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223-226.


3. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2: 217-218.


4. Gabor EP. Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997; 127:1130.


5. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986; 26:410-412.


6. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789.


7. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997; 20:1142-1145.


8. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129-135.


9. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264-268.


10. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17:241-251.


11. Siber GA, Werner BG, Halsey NA, Reid R, Almeido-Hill J, Garrett SC, Thompson C, Santosham M. Interference of immune globulin with measles and rubella immunization. J Pediatr 1993; 122:204-211.


12. Salisbury D, Ramsay M, Noakes K, eds. Immunisation against infectious disease. The Stationery Office (TSO), London: UK Department of Health, 2009; p426,


13. Hammarström L, Smith CIE. Placental transfer of intravenous immunoglobulin. Lancet 1986; 1:681.


14. Sidiropoulos D, Herrmann U, Morell A, von Muralt G, Barandun S. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986; 109:505-508.


15. Wood P, Stanworth S, Burton J, Jones A, Peckham DG, Chapel H. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol 2007; 149:410-423.


16. Simon H, Späth P. IVIG – Mechanisms of action. Allergy 2003; 58(7):543-52.


17. Center for Biologics Evaluation and Research. Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency. Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration; July, 2008.

How Supplied/Storage and Handling

Gammaplex is supplied in a single use, clear Type II glass bottle, closed with a stopper (13% natural rubber) and oversealed with a tamper-evident cap.

The following presentations of Gammaplex are available:

NDC Number	Grams and Fill Size
64208-8234-1	2.5g in 50 mL
64208-8234-2	5 g in 100 mL
64208-8234-3	10 g in 200 mL

Each vial has a label with a peel-off strip showing the product name and batch number.

When stored between 2 °C [35.6 °F] and 25 °C [77 °F]), Gammaplex has a shelf life of 24 months, as indicated by the expiration date printed on the outer carton and vial label.

Keep Gammaplex in its original carton to protect it from light.

DO NOT FREEZE.

Patient Counseling Information

Inform patients to immediately report the following signs and symptoms to their healthcare professional:

• Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see Warnings and Precautions [5.2]).


• Acute chest pain, shortness of breath, leg pain, and swelling of the legs/feet (see Warnings and Precautions [5.4]).


• Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea and vomiting (see Warnings and Precautions [5.5]).


• Increased heart rate, fatigue, yellowing of skin or eyes, dark-colored urine (see Warnings and Precautions [5.6]).


• Trouble breathing, chest pain, blue lips or extremities, fever (see Warnings and Precautions [5.7]).

Inform patients that Gammaplex is made from human plasma and may contain infectious agents that can cause disease. While the risk that Gammaplex can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them (see Warnings and Precautions [5.8]).

Inform patients that Gammaplex can interfere with their immune response to live viral vaccines (e.g., measles, mumps, and rubella), and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations (see Drug Interactions [7]).

Manufactured by:

Bio Products Laboratory

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

US License No. 1811

U.S. Distributor:

FFF Enterprises, Inc.

41093 County Center Drive

Temecula, California 92591

U.S.A.

Bio Products Laboratory

Dagger Lane, Elstree, Herts., WD6 3BX, U.K.

Tel: + 44 (0) 20 8258 2200

DATE OF LEAFLET PREPARATION September 2009

VSUS1PI

PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton

Immune Globulin

Intravenous (Human)

5 g

100 mL

Gammaplex®

SOLUTION FOR INFUSION

FOR INTRAVENOUS USE

ONLY

RX ONLY

Manufactured by:

Bio Products Laboratory

Dagger Lane, Elstree,

Herts WD6 3BX U.K.

U.S. License No. 1811

bpL

Bio Products Laboratory

PRINCIPAL DISPLAY PANEL - 200 mL Bottle Carton

Immune Globulin

Intravenous (Human)

10 g

200 mL

Gammaplex®

SOLUTION FOR INFUSION

FOR INTRAVENOUS USE

ONLY

RX ONLY

Manufactured by:

Bio Products Laboratory

Dagger Lane, Elstree,

Herts WD6 3BX U.K.

U.S. License No. 1811

bpL

Bio Products Laboratory

Gammaplex  human immunoglobulin g  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64208-8234 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength

magnesium salicylate

Generic Name: magnesium salicylate (mag NEE zee um sa LIS i late)

Brand names: MST, Nuprin Backache Caplet, Magan, Mobidin, Doans Pills, Bayer Select Backache Pain Formula, Doans Pills Extra Strength

What is magnesium salicylate?

Magnesium salicylate is a non-steroidal anti-inflammatory drug (NSAID) in a group of drugs called salicylates (sa-LIS-il-ates). This medicine works by reducing substances in the body that cause pain, fever, and inflammation.

Magnesium salicylate is used to reduce pain, swelling, and joint stiffness caused by arthritis.

Magnesium salicylate may also be used for purposes not listed in this medication guide.

What is the most important information I should know about magnesium salicylate?

You should not use this medication if you are allergic to aspirin or to an NSAID (non-steroidal anti-inflammatory drug), or if you have recently used cidofovir (Vistide) or ketorolac (Toradol).

Before taking magnesium salicylate, tell your doctor if you have asthma, heart disease, high blood pressure, stomach or intestinal bleeding, diabetes, anemia, a bleeding disorder, liver or kidney disease, nasal polyps, a genetic enzyme deficiency, or if you are dehydrated.

This medicine may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term. Do not use magnesium salicylate just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Get emergency medical help if you have chest pain, weakness, shortness of breath, slurred speech, or problems with vision or balance.

This medicine may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning while you are taking magnesium salicylate, especially in older adults.

Call your doctor at once if you have symptoms of stomach bleeding such as black, bloody, or tarry stools, or coughing up blood or vomit that looks like coffee grounds. This medication should not be given to a child or teenager who has a fever, especially if the child also has flu symptoms or chicken pox. Salicylates can cause a serious and sometimes fatal condition called Reye's syndrome in children.

What should I discuss with my healthcare provider before taking magnesium salicylate?

Do not use magnesium salicylate just before or after heart bypass surgery (coronary artery bypass graft, or CABG). You should not use this medication if you are allergic to aspirin or to an NSAID (non-steroidal anti-inflammatory drug), or if you have recently used:

• 
  

  cidofovir (Vistide); or

  
  


• 
  

  ketorolac (Toradol).

  
  

Magnesium salicylate may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term.

Magnesium salicylate may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning while you are taking this medicine, especially in older adults.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• kidney disease;


• 
  

  asthma;

  
  


• 
  

  heart disease, high blood pressure, congestive heart failure;

  
  


• 
  

  a history of stroke or heart attack;

  
  


• 
  

  a stomach ulcer or intestinal bleeding;

  
  


• 
  

  a bleeding or blood clotting disorder;

  
  


• 
  

  diabetes;

  
  


• 
  

  swelling or fluid retention;

  
  


• 
  

  anemia (a lack of red blood cells);

  
  


• liver disease;


• 
  

  an enzyme deficiency called glucose-6-phosphate dehydrogenase deficiency (G6PD);

  
  


• 
  

  nasal polyps; or

  
  


• 
  

  if you are dehydrated.

  
  

FDA pregnancy category C. Magnesium salicylate may be harmful to an unborn baby if the mother takes the medication during the last 3 months of pregnancy. Do not take this medication without telling your doctor if you are pregnant or plan to become pregnant during treatment. Magnesium salicylate can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. This medication should not be given to a child or teenager who has a fever, especially if the child also has flu symptoms or chicken pox. Salicylates can cause a serious and sometimes fatal condition called Reye's syndrome in children. Older adults may be more likely to have side effects from magnesium salicylate.

How should I take magnesium salicylate?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Magnesium salicylate may be taken up to 4 times per day. Follow your doctor's instructions.

Take the medicine with a full glass of water. Take magnesium salicylate with food, milk, or an antacid if it upsets your stomach. To prevent stomach upset, do not lie down for at least 30 minutes after taking the medication. It may take up to 2 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 2 weeks of treatment.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using magnesium salicylate.

If you need surgery, tell the surgeon ahead of time that you are using magnesium salicylate. You may need to stop using the medicine for a short time. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Since magnesium salicylate is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include ringing in your ears, severe dizziness or drowsiness, weakness, nausea, vomiting, confusion, fast breathing, or seizure (convulsions).

What should I avoid while taking magnesium salicylate?

If you also take an antibiotic, avoid taking it within 2 hours before or after you take magnesium salicylate. This medication can make it harder for your body to absorb certain antibiotics. Ask a doctor or pharmacist before using any other over-the-counter medication. Salicylates and NSAIDs are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains aspirin, ibuprofen, naproxen, ketoprofen, magnesium salicylate, or similar medicines.

If you are also taking low-dose aspirin because your doctor has prescribed it to prevent heart attack or stroke, do not stop taking it or change your dose without your doctor's advice. Aspirin should be used for cardiovascular conditions only under the supervision of a doctor.

Avoid drinking alcohol. It may increase your risk of stomach bleeding. Avoid smoking, since it can also increase your risk of stomach bleeding.

Magnesium salicylate side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  chest pain, severe dizziness, shortness of breath, slurred speech, problems with vision or balance;

  
  


• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  black, bloody, or tarry stools;

  
  


• 
  

  coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  blood in your urine, urinating more or less than usual;

  
  


• 
  

  hearing problems, ringing in your ears;

  
  


• 
  

  swelling, rapid weight gain;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, sore throat, flu symptoms;

  
  


• 
  

  fast or pounding heartbeats;

  
  


• 
  

  severe stomach pain, ongoing nausea or vomiting; or

  
  


• 
  

  dark urine, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  heartburn; or

  
  


• 
  

  upset stomach.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect magnesium salicylate?

Many drugs can interact with magnesium salicylate. Below is just a partial list. Tell your doctor if you are using:

• 
  

  acetazolamide (Diamox);

  
  


• 
  

  cyclosporine (Gengraf, Neoral, Sandimmune);

  
  


• 
  

  gabapentin (Neurontin);

  
  


• 
  

  lithium (Eskalith, LithoBid);

  
  


• 
  

  methotrexate (Rheumatrex, Trexall);

  
  


• 
  

  milk of magnesia;

  
  


• 
  

  pemetrexed (Alimta);

  
  


• 
  

  tenofovir (Viread);

  
  


• 
  

  an antidepressant such as fluoxetine (Prozac) or sertraline (Zoloft);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  oral diabetes medication;

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  gout medication such as probenecid (Benemid);

  
  


• 
  

  heart or blood pressure medication such as atenolol (Tenormin), captopril (Capoten), lisinopril (Prinivil, Zestril), losartan (Cozaar, Hyzaar), metoprolol (Lopressor, Toprol), and others;

  
  


• 
  

  medication used to prevent blood clots, such as cilostazol (Pletal) or clopidogrel (Plavix);

  
  


• 
  

  osteoporosis medication such as alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel), and others;

  
  


• 
  

  seizure medication such as phenytoin (Dilantin), phenobarbital (Solfoton), valproic acid (Depakene); or

  
  


• 
  

  steroid medicine such as danazol (Danocrine), oxandrolone (Oxandrin), prednisone, and others.

  
  

This list is not complete and there are many other drugs that can interact with magnesium salicylate. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More magnesium salicylate resources

• Magnesium salicylate Side Effects (in more detail)
• Magnesium salicylate Use in Pregnancy & Breastfeeding
• Magnesium salicylate Drug Interactions
• Magnesium salicylate Support Group
• 0 Reviews for Magnesium salicylate - Add your own review/rating

• Magnesium Salicylate MedFacts Consumer Leaflet (Wolters Kluwer)

Compare magnesium salicylate with other medications

• Inflammatory Conditions
• Pain

Where can I get more information?

• Your pharmacist can provide more information about magnesium salicylate.

See also: magnesium salicylate side effects (in more detail)

lurasidone

Generic Name: lurasidone (loo RAS i done)

Brand Names: Latuda

What is lurasidone?

Lurasidone is an antipsychotic medication. It works by changing the effects of chemicals in the brain.

Lurasidone is used to treat schizophrenia in adults.

Lurasidone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about lurasidone?

Lurasidone is not for use in psychotic conditions related to dementia. Lurasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions. You should not use this medication if you are allergic to lurasidone, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

Before you take lurasidone, tell your doctor if you have liver disease, kidney disease, heart disease, high blood pressure, heart rhythm problems, a history of heart attack or stroke, high cholesterol or triglycerides, low white blood cell (WBC) counts, seizures, diabetes, Parkinson's disease, trouble swallowing, or a history of breast cancer or suicidal thoughts.

While you are taking lurasidone, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking lurasidone. Lurasidone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Drinking alcohol can increase certain side effects of lurasidone. Stop using lurasidone and call your doctor at once if you have very stiff (rigid) muscles, high fever, sweating, confusion, fast or pounding heartbeats, feeling like you might pass out, tremors, or twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

There are many other drugs that can interact with lurasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

What should I discuss with my healthcare provider before taking lurasidone?

Lurasidone is not for use in psychotic conditions related to dementia. Lurasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions. You should not use this medication if you are allergic to lurasidone, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

To make sure you can safely take lurasidone, tell your doctor if you have any of these other conditions:

• liver disease;


• 
  

  kidney disease;

  
  


• 
  

  heart disease, high blood pressure, heart rhythm problems;

  
  


• 
  

  a history of heart attack or stroke;

  
  


• 
  

  high cholesterol or triglycerides (a type of fat in the blood);

  
  


• 
  

  low white blood cell (WBC) counts;

  
  


• 
  

  a history of breast cancer;

  
  


• 
  

  seizures or epilepsy;

  
  


• 
  

  personal or family history of diabetes (lurasidone may raise your blood sugar);

  
  


• 
  

  a history of suicidal thoughts or actions;

  
  


• 
  

  Parkinson's disease; or

  
  


• 
  

  trouble swallowing.

  
  

Lurasidone may cause you to have high blood sugar (hyperglycemia). Talk to your doctor if you have any signs of hyperglycemia such as increased thirst or urination, excessive hunger, or weakness. If you are diabetic, check your blood sugar levels on a regular basis while you are taking lurasidone.

FDA pregnancy category B. Lurasidone is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether lurasidone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using lurasidone.

Do not give this medication to a child without medical advice.

How should I take lurasidone?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Lurasidone should be taken with food (at least 350 calories).

Use lurasidone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

It may take several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve. Store at room temperature away from moisture and heat.

See also: Lurasidone dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

What should I avoid while taking lurasidone?

While you are taking lurasidone, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking lurasidone. Lurasidone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of lurasidone.

Lurasidone side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking lurasidone and call your doctor at once if you have a serious side effect such as:

• 
  

  dizziness, fainting, fast or pounding heartbeats;

  
  


• 
  

  agitation, hostility, confusion, thoughts about hurting yourself;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  fever, chills, body aches, flu symptoms, sores in your mouth and throat;

  
  


• 
  

  high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss);

  
  


• 
  

  very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out;

  
  


• 
  

  trouble swallowing; or

  
  


• 
  

  twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

  
  

Less serious side effects may include:

• 
  

  drowsiness;

  
  


• 
  

  feeling restless;

  
  


• 
  

  nausea, diarrhea, stomach pain, loss of appetite;

  
  


• 
  

  blurred vision;

  
  


• 
  

  weight gain;

  
  


• 
  

  breast swelling or discharge;

  
  


• 
  

  missed menstrual periods; or

  
  


• 
  

  decreased sex drive, impotence, or difficulty having an orgasm.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Lurasidone Dosing Information

Usual Adult Dose for Schizophrenia:

40 mg orally once daily. Initial dose titration is not required. The maximum recommended dose is 80 mg once daily.

What other drugs will affect lurasidone?

Before you take lurasidone, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by lurasidone.

Many drugs can interact with lurasidone. Below is just a partial list. Tell your doctor if you are using:

• 
  

  bosentan (Tracleer);

  
  


• 
  

  conivaptan (Vaprisol);

  
  


• 
  

  dexamethasone (Decadron, Hexadrol);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  isoniazid (for treating tuberculosis);

  
  


• 
  

  St. John's wort;

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), rifapentine (Priftin), or telithromycin (Ketek);

  
  


• 
  

  antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);

  
  


• 
  

  an antidepressant such as nefazodone;

  
  


• 
  

  heart or blood pressure medication such as diltiazem (Cartia, Cardizem), nicardipine (Cardene), quinidine (Quin-G), verapamil (Calan, Covera, Isoptin, Verelan), and others;

  
  


• 
  

  HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva, Atripla), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), saquinavir (Invirase), or ritonavir (Norvir, Kaletra);

  
  


• 
  

  medicines to treat narcolepsy, such as armodafanil (Nuvigil) or modafanil (Progivil); or

  
  


• 
  

  seizure medication such as carbamazepine (Carbatrol, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenobarbital (Solfoton), phenytoin (Dilantin), or primidone (Mysoline).

  
  

This list is not complete and other drugs may interact with lurasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More lurasidone resources

• Lurasidone Side Effects (in more detail)
• Lurasidone Dosage
• Lurasidone Use in Pregnancy & Breastfeeding
• Lurasidone Drug Interactions
• Lurasidone Support Group
• 33 Reviews for Lurasidone - Add your own review/rating

• lurasidone Advanced Consumer (Micromedex) - Includes Dosage Information


• Lurasidone MedFacts Consumer Leaflet (Wolters Kluwer)


• Latuda Prescribing Information (FDA)


• Latuda Consumer Overview


• Latuda Monograph (AHFS DI)

Compare lurasidone with other medications

• Bipolar Disorder
• Borderline Personality Disorder
• Schizoaffective Disorder
• Schizophrenia

Where can I get more information?

• Your pharmacist can provide more information about lurasidone.

See also: lurasidone side effects (in more detail)