FORAVEN XL 75mg modified release capsules

1. Name Of The Medicinal Product

FORAVEN XL 75mg modified release capsules

2. Qualitative And Quantitative Composition

FORAVEN XL 75mg modified release capsules contain 84.8mg of venlafaxine hydrochloride, equivalent to 75mg of venlafaxine free base, in an extended release formulation.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Modified release capsules, hard. The capsules are opaque peach having a thick and a thin radial circular band on the body in red ink and a thick and a thin radial circular band on the cap in red ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Major depressive disorder

FORAVEN XL 75mg modified release capsules are indicated for the treatment of major depressive disorder including depression accompanied by anxiety. All patients should be evaluated for the risk of suicidality and monitored for clinical worsening (see section 4.2 and 4.4).

Following an initial response venlafaxine capsules are indicated for the prevention of relapses of the initial episode of depression or for the prevention of the recurrence of new episodes.

4.2 Posology And Method Of Administration

Depression

The recommended dose is 75mg per day given once daily. Most patients respond to this dose.

If, after an adequate trial and evaluation, further clinical improvement is required, the dose may be increased to 150mg per day given once daily. There may be an increased risk of side effects at higher doses and dose increments should be made only after a clinical evaluation and after at least 3-4 weeks of therapy (see section 4.4). The lowest effective dose should be maintained.

In more severely depressed or hospitalised patients, and under close supervision of a physician, the daily dose may then be increased to the maximum recommended dose of FORAVEN XL capsules, 375mg given once daily. In those more severely depressed or hospitalised patients who require daily venlafaxine doses of 300mg or more, treatment with venlafaxine tablets should be initiated under specialist supervision including shared care arrangements.

The dose should then be gradually reduced, to the minimum effective dose consistent with patient response and tolerance. A limited amount of venlafaxine should be provided to reduce the risk from overdose (see section 4.4).

Usually, the dosage for prevention of relapse or for prevention of recurrence of a new episode is similar to that used during the index episode. Patients should be re-assessed regularly in order to evaluate the benefit of long-term therapy.

Use in elderly patients

No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treating the elderly (e.g. due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required.

Use in children and adolescents under the age of 18 years

Venlafaxine is not recommended for use in children and adolescents.

Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8).

The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 have not been established.

Patients with increased risk for suicide (see also sections 4.4 and 4.9)

Patients with increased risk factors for suicide should be carefully evaluated for the presence or worsening of suicide-related behaviour (see sections 4.4 and 4.9) and a limited number of capsules should be provided to reduce the risk from overdose. A maximum of two weeks supply should be considered in these patients at initiation of treatment, during any dosage adjustment and until improvement occurs.

Use in patients with hepatic impairment

In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable.

There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50% should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment.

Use in patients with renal impairment

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable.

Maintenance/continuation/extended treatment

The physician should periodically re-evaluate the usefulness of long-term treatment with venlafaxine modified release capsules for the individual patient. It is generally agreed that acute episodes of major depression require several months or longer of sustained therapy. Venlafaxine has been shown to be efficacious during long-term (up to 12 months) treatment.

In clinical trials venlafaxine was demonstrated to be effective for preventing relapse, or recurrence of new episodes, in patients responding to venlafaxine treatment during the index episode.

Withdrawal symptoms seen on discontinuation of venlafaxine

Abrupt discontinuation should be avoided. When stopping treatment with venlafaxine, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

For oral use.

It is recommended that venlafaxine prolonged-release capsules be taken with food, at approximately the same time each day. Capsules must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

Patients treated with venlafaxine immediate-release tablets may be switched to venlafaxine prolonged-release capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5 mg twice daily may be switched to venlafaxine prolonged-release capsules 75 mg once daily. Individual dosage adjustments may be necessary.

Venlafaxine prolonged-release capsules contain mini-tablets, which release the active substance slowly into the digestive tract. The insoluble coating of these mini-tablets is eliminated and may be seen in faeces.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI.

Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4 and 4.5).

4.4 Special Warnings And Precautions For Use

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which venlafaxine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients, and in particular those at high risk, should accompany drug therapy, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour, and to seek medical advice immediately if these symptoms present.

Use in children and adolescents under 18 years of age

Venlafaxine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

Concomitant use of neuroleptics

As with SSRIs, venlafaxine should be used with caution in patients already receiving neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination.

Narrow-angle glaucoma

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) be closely monitored.

Blood pressure

Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before initiation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.

Postural hypotension

Postural hypotension has been observed occasionally during venlafaxine treatment. Patients, especially the elderly, should be alerted to the possibility of dizziness or unsteadiness.

Heart rate

Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Cardiac disease and risk of arrhythmia

Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.

In post-marketing experience, fatal cardiac arrhythmias have been reported with the use of venlafaxine especially in overdose. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia.

Convulsions

Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions, and concerned patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.

Hyponatraemia

Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine. This has most frequently been reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.

Abnormal bleeding

Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. The risk of skin and mucous membrane bleeding, including gastrointestinal haemorrhage may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients pre-disposed to bleeding, including patients on anticoagulants and platelet inhibitors.

Serum cholesterol

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol should be considered during long-term treatment.

Co-administration with weight loss agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Mania/hypomania

Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression

Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Possibility of drug abuse

Due to the possibility of drug abuse with CNS-active drugs, physicians should evaluate patients for a history of drug abuse, and follow such patients closely. Clinical studies have shown no evidence of drug-seeking behaviour, development of tolerance, or dose escalation over time among patients taking venlafaxine.

Discontinuation of treatment

Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients taking placebo.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patients needs (see section 4.2).

Akathisia / psychomotor restlessness

The use of venlafaxine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Dry mouth

Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.

Diabetes

In patients with diabetes, treatment with an SSRI or venlafaxine may alter glycaemic control. Insulin and/or oral anti-diabetic dosage may need to be adjusted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine Oxidase Inhibitors (MAOI)

Irreversible non-selective MAOIs

Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI (see sections 4.3 and 4.4).

Reversible, selective MAOI-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO inhibitor a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wart (Hypericum perforatum), with medicinal agents which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

If concomitant treatment of venlafaxine with an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

CNS active substances

The risk of using venlafaxine in combination with other CNS-active substances has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS-active substances.

Ethanol

Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CVP2D6 PM and EM subjects respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritanovir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

Cimetidine

Cimetidine inhibited the first-pass metabolism of venlafaxine but had no significant effect on the formation or elimination of O-desmethylvenlafaxine, which is present in much greater quantities in the systemic circulation. No dosage adjustment therefore seems necessary when venlafaxine is co-administered with cimetidine. For elderly patients, or patients with hepatic dysfunction the interaction could potentially be more pronounced, and for such patients clinical monitoring is indicated when venlafaxine is administered with cimetidine.

Effect of venlafaxine on other medicinal products

Lithium

Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see Serotonin syndrome).

Diazepam

Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine.

Haloperidol

A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in C_max, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly. The clinical significance of this interaction is unknown.

Risperidone

Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Metoprolol

Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.

Indinavir

A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

Clozapine

Increased levels of clozapine, that were temporally associated with adverse events, including seizures, have been reported following the addition of venlafaxine.

Warfarin

Potentiation of anticoagulant effects including increases in PT or INR have been reported in patients taking warfarin following the addition of venlafaxine.

ECT

There is little clinical experience of the concurrent use of venlafaxine with ECT. As prolonged seizure activity has been reported with concomitant SSRI antidepressants, caution is advised.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of venlafaxine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.

As with other serotonin reuptake inhibitors (SSRIs/SNRIs), discontinuation symptoms may occur in the newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with FORAVEN XL capsules taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

The following symptoms may be observed in neonates if the mother has used an SSRI/SNRI late in pregnancy; irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or sleeping. These symptoms may be due to either serotonergic effects or exposure symptoms. In the majority of cases, these complications are observed immediately or within 24 hours after partus.

Lactation

Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. There have been post-marketing reports of breast-fed infants who experienced crying, irritability, and abnormal sleep patterns. Symptoms consistent with venlafaxine drug discontinuation have also been reported after stopping breastfeeding. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast-feeding or to continue/discontinue therapy with venlafaxine should be made, taking into account the benefit of breast-feeding to the child and the benefit of venlafaxine therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Any psychoactive medicinal product may impair judgment, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.

4.8 Undesirable Effects

See also Special Warnings and Special Precautions for Use.

The most commonly (>1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).

Adverse reactions are listed below by system organ class and frequency.

Frequencies are defined as: very common (

Body system	Very Common	Common	Uncommon	Rare	Not known
Haematological/ Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopaenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia and pancytopaenia)
Metabolic/ Nutritional		Serum cholesterol increased, Weight loss	Weight gain		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Prolactin increased
Nervous	Dry mouth (10%), Headache (30.3%)*	Abnormal dreams, Decreased libido, Dizziness, Increased muscle tonus (hypertonia), Insomnia, Nervousness, Paresthesia, Sedation, Tremor, Confusion, Depersonalisation	Apathy, Hallucinations, Myoclonus, Agitation, Impaired coordination and balance	Akathisia/ Psychomotor restlessness, Convulsion, Manic reaction	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramidal reactions (including dystonia and dyskinesia), Tardive dyskinesia, Suicidal ideation and behaviours**, Vertigo, Aggression***
Special senses		Abnormality of accommodation, Mydriasis, Visual disturbance	Altered taste sensation, Tinnitus		Angle-closure glaucoma
Cardiovascular		Hypertension, Vasodilation (mostly hot flashes/flushes), Palpitations	Postural hypotension, Syncope, Tachycardia		Hypotension, QT prolongation, Ventricular fibrillation, Ventricular tachycardia (including torsades de pointes)
Respiratory		Yawning			Pulmonary eosinophilia
Digestive	Nausea (20.0%)	Appetite decreased (anorexia), Constipation, Vomiting	Bruxism, Diarrhoea		Pancreatitis
Skin	Sweating (including night sweats) [12.2%]		Rash, Alopecia		Erythema multiforme, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria
Musculoskeletal					Rhabdomyolysis
Urinogenital		Abnormal ejaculation/orgasm (males), Anorgasmia, Erectile dysfunction (impotence), Urination impaired (mostly hesitancy), Menstrual disorders associated with increased or increased irregular bleeding (e.g. menorrhagia, metrorrhagia), Pollakiuria	Abnormal orgasm (females), Urinary retention	Urinary incontinence
Body as a whole		Asthenia (fatigue), Chills	Angioedema, Photosensitivity reaction		Anaphylaxis

*In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with placebo.

**Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4)

***See section 4.4.

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache and flu syndrome are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients, they may be severe and/or prolonged. It is therefore advised that when venlafaxine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Paediatric patients

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed (see section 4.4).

In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm.

Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

Special notes

In all pre-marketing depression trials with venlafaxine tablets, seizures were reported in 0.3% of all venlafaxine-treated patients (see section 4.4).

Nausea is most common at the start of treatment with the incidence decreasing over the first few weeks.

4.9 Overdose

In post-marketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other medicinal products. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, vertigo, and death.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of the medicinal product consistent with good patient management in order to reduce the risk of overdose.

Recommended treatment

General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

5. Pharmacological Properties

Pharmacotherapeutic group: Other antidepressants - ATC code: NO6A X16.

5.1 Pharmacodynamic Properties

The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Studies in animals show that tricyclic antidepressants may reduce β-adrenergic responsiveness following chronic administration. In contrast, venlafaxine and its active metabolite reduced β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake.

Venlafaxine has virtually no affinity for rat brain muscarinic cholinergic, H₁-histaminergic or α₁-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant drugs, such as anticholinergic, sedative and cardiovascular side effects.

Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-d-aspartic acid (NMDA) receptors. It has no significant central nervous system (CNS) stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant or depressant abuse liability.

5.2 Pharmacokinetic Properties

At least 92% of a single oral dose of venlafaxine is absorbed. After administration of an extended release formulation dose, the peak plasma concentrations of venlafaxine and ODV are attained within 6.0±1.5 and 8.8 ±2.2 hours, respectively. The rate of absorption of venlafaxine from the extended release formulation capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of such extended release formulation capsule (15± 6 hours) is actually the absorption half-life instead of the true disposition half-life (5±2 hours) observed following administration of an immediate release tablet.

When equal daily doses of venlafaxine were administered as either the immediate release tablet, or the modified/extended release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the modified/extended release capsule. Therefore, the modified/extended release capsule provides a slower rate of absorption, but the same extent of absorption (i.e. AUC), as the immediate release tablet.

Venlafaxine undergoes extensive first-pass metabolism in the liver, primarily by CYP2D6, to the major metabolite ODV. Venlafaxine is also metabolised to N-desmethylvenlafaxine, catalysed by CYP3A3/4, and to other minor metabolites.

Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine, unconjugated ODV, conjugated ODV, or other minor metabolites.

The half-lives of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) are increased in patients with renal and hepatic impairment.

Administration of the modified/extended release capsules with food has no effect on the absorption of venlafaxine, or on the subsequent formation of ODV.

Subject age and sex do not significantly affect the pharmacokinetics of venlafaxine. No accumulation of venlafaxine or ODV has been observed during chronic administration in healthy subjects.

Venlafaxine 75mg modified release capsules contain mini-tablets; the coating of those mini-tablets is extended-release coating.

5.3 Preclinical Safety Data

Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis. Venlafaxine was not mutagenic in a wide range of in vitro and in vivo tests.

Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose E460

Povidone E1201

Talc E553b

Colloidal anhydrous silica

Magnesium stearate E470b

Ethylcellulose E462

Copovidone

Capsule shell components

Gelatine

Titanium dioxide E171

Black and red iron oxide E172

Printing ink

Shellac E904

Propylene glycol E1520

Red iron oxide E172

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store in the original package to protect from moisture. Do not store above 25°C.

6.5 Nature And Contents Of Container

PVC-ACLAR/aluminium foil blister strips containing 14 capsules. Two of such strips are packaged in a carton.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Forum Products Limited

57-65 Station Road

Redhill

Surrey

RH1 1DL

FORAVEN XL 75mg modified release capsules are marketed in a trading style (Quantum Generics) of the MA holder.

Jeracin

Jeracin may be available in the countries listed below.

Ingredient matches for Jeracin

Erythromycin

Erythromycin is reported as an ingredient of Jeracin in the following countries:

• Indonesia

International Drug Name Search

Aristocort A Cream

Pronunciation: TRY-am-SIN-oh-lone ah-SEE-toe-nide
Generic Name: Triamcinolone
Brand Name: Examples include Aristocort A and Kenalog

Aristocort A Cream is used for:

Reducing itching, redness, and swelling associated with many skin conditions.

Aristocort A Cream is a corticosteroid. The exact way that it acts against most causes of inflammation is not known, but it is thought to slow or stop the chemicals in the body that cause inflammation. This helps to relieve discomfort.

Do NOT use Aristocort A Cream if:

• you are allergic to any ingredient in Aristocort A Cream

Contact your doctor or health care provider right away if any of these apply to you.

Before using Aristocort A Cream:

Some medical conditions may interact with Aristocort A Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a skin infection, measles, thinning of the skin, tuberculosis (TB), a positive TB skin test, chickenpox, shingles, or have recently had a vaccination

Some MEDICINES MAY INTERACT with Aristocort A Cream. Because little, if any, of Aristocort A Cream is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Aristocort A Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Aristocort A Cream:

Use Aristocort A Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Apply a small amount of medicine to the affected area. Gently rub the medicine in until it is evenly distributed. Wash your hands after applying Aristocort A Cream, unless your hands are part of the treated area.


• Do not wrap or otherwise cover the treated area with bandages or wear tight-fitting clothing unless specifically directed to do so by your doctor. Do not use tight-fitting diapers or plastic pants on children using Aristocort A Cream in the diaper area.


• If you miss a dose of Aristocort A Cream, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Ask your health care provider any questions you may have about how to use Aristocort A Cream.

Important safety information:

• Aristocort A Cream is for external use only. If you get Aristocort A Cream in your eyes, immediately flush with cool tap water.


• Do not use Aristocort A Cream for other skin conditions at a later time.


• Corticosteroids may affect growth rate in CHILDREN and teenagers in some cases. They may need regular growth checks while they use Aristocort A Cream.


• Caution is advised when using Aristocort A Cream in CHILDREN; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Aristocort A Cream while you are pregnant. It is unknown if Aristocort A Cream is found in breast milk. If you are or will be breast-feeding while you use Aristocort A Cream, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Aristocort A Cream:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Aristocort A Cream. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurry vision;changes in menstrual cycle; easy bruising; excessive hair growth; impaired wound healing; itching, burning, redness, discoloration, or swelling of the skin not present before using Aristocort A Cream; mental or mood changes; moon face; muscle weakness; osteoporosis; rise in body temperature; skin thinning; tiredness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Aristocort A side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Aristocort A Cream may be harmful if swallowed.

Proper storage of Aristocort A Cream:

Store Aristocort A Cream at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, light, and moisture. Keep Aristocort A Cream out of the reach of children and away from pets.

General information:

• If you have any questions about Aristocort A Cream, please talk with your doctor, pharmacist, or other health care provider.


• Aristocort A Cream is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Aristocort A Cream. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Aristocort A resources

• Aristocort A Side Effects (in more detail)
• Aristocort A Use in Pregnancy & Breastfeeding
• Aristocort A Drug Interactions
• Aristocort A Support Group
• 1 Review for Aristocort A - Add your own review/rating

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Cambia

diclofenac potassium

Dosage Form: powder, for oral solution
FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Risk

Non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)].

Cambia is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

Gastrointestinal Risk

NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)].

      INDICATIONS AND USAGE

Acute Treatment of Migraine

      Cambia™ (Diclofenac Potassium for Oral Solution) is indicated for the acute treatment of migraine attacks with or without aura in adults (18 years of age or older).

Important Limitations

• Cambia is not indicated for the prophylactic therapy of migraine.
  


• The safety and effectiveness of Cambia have not been established for cluster headache, which is present in an older, predominantly male population.

      DOSAGE AND ADMINISTRATION      

Acute Treatment of Migraine

      Administer one packet (50 mg) of Cambia™  for the acute treatment of migraine. Empty the contents of one packet into a cup containing 1 to 2 ounces (30 to 60 mL) of water, mix well and drink immediately. Do not use liquids other than water.

      Taking Cambia with food may cause a reduction in effectiveness compared to taking Cambia on an empty stomach [see Clinical Pharmacology (12.3)].

      Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.  The safety and effectiveness of a second dose have not been established.

Interchangeability With Other Formulations of Diclofenac

      Different formulations of oral diclofenac (e.g., Cambia, diclofenac sodium enteric-coated tablets, diclofenac sodium extended-release tablets, or diclofenac potassium immediate-release tablets) may not be bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulation of diclofenac to Cambia.

     

      DOSAGE FORMS AND STRENGTHS

      Cambia   is available in individual packets each designed to deliver a 50 mg dose when mixed in water.

      CONTRAINDICATIONS

• Cambia is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to diclofenac [see Warnings and Precautions (5.7, 5.8)].
  


• Cambia is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.12)].
  


• Cambia is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].

      WARNINGS AND PRECAUTIONS

Cardiovascular Thrombotic Events

      Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years’ duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Inform patients about the signs and symptoms of serious CV events and the steps to take if they occur.

      There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID increases the risk of serious GI events [see Warnings and Precautions (5.2)].

      Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)].

       

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

      NSAIDs, including Cambia, can cause serious gastrointestinal (GI) adverse events such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term NSAID therapy is not without risk.

      Prescribe NSAIDs, including Cambia, with extreme caution in patients with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.

      To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during Cambia therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the Cambia until a serious GI adverse event is ruled out. For high risk patients, alternative therapies that do not include NSAIDs should be considered.

Hepatic Effects

      Elevations of one or more liver tests may occur during therapy with Cambia. These laboratory abnormalities may progress, may persist, or may only be transient with continued therapy. Borderline elevations (less than 3 times the upper limit of the normal [ULN] range) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

      In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during treatment (ALT was not measured in all studies). In an open-label, controlled trial of 3,700 patients treated for 2–6 months, patients were monitored at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (>8 times the ULN) in about 1% of the 3,700 patients. In this open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3–8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs..  Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

      Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac.

      Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

            Measure transaminases (ALT and AST) periodically in patients receiving long-term therapy with diclofenac because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue Cambia immediately.

      To minimize the possibility that hepatic injury will become severe between transaminase measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients should take if these signs and symptoms appear.

      To minimize the potential risk for an adverse liver-related event in patients treated with Cambia, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Cambia with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, antiepileptics). Caution patients to avoid taking nonprescription acetaminophen-containing products while using Cambia.

Hypertension

      NSAIDs, including Cambia, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including Cambia, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy.

      Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs. 

Congestive Heart Failure and Edema

      Fluid retention and edema have been observed in some patients taking NSAIDs. Use Cambia with caution in patients with fluid retention or heart failure.

Renal Effects

      Use caution when initiating treatment with Cambia in patients with considerable dehydration.

      Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

      No information is available from controlled clinical studies regarding the use of Cambia in patients with advanced renal disease. Therefore, treatment with Cambia is not recommended in patients with advanced renal disease. If Cambia therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

      As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Cambia. Cambia is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. [see Contraindications (4)].

Serious Skin Reactions

      NSAIDs, including Cambia, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations and to discontinue Cambia at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

      Cambia can cause fetal harm when administered to a pregnant woman. Starting at 30 weeks gestation, Cambia and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus [see Use in Special Populations (8.1)].

Masking of Inflammation and Fever

      The pharmacological activity of NSAIDs in reducing inflammation and possibly fever may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hematologic Effects

      Anemia may occur in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term therapy with NSAIDs, including Cambia, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss.

      NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, the NSAID effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with Cambia who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

Use in Patients With Pre-existing Asthma

      Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Cambia is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.

Monitoring

      Because serious GI ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

      For patients on long-term treatment with NSAIDs, including Cambia, periodically perform a CBC and chemistry profile. Discontinue Cambia if abnormal liver tests or renal tests persist or worsen.

Phenylketonurics

      Cambia contains aspartame equivalent to phenylalanine 25 mg per packet.

      ADVERSE REACTIONS

      The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.1)]
  


• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]
  


• Hepatic effects [see Warnings and Precautions (5.3)]
  


• Hypertension [see Warnings and Precautions (5.4)]
  


• Congestive Heart Failure and Edema [see Warnings and Precautions (5.5)]
  


• Renal Effects  [see Warnings and Precautions (5.6)]
  


• Anaphylactoid Reactions [see Warnings and Precautions (5.7)]
  


• Serious Skin Reactions [see Warnings and Precautions (5.8)]

      The most common adverse reactions reported with Cambia are nausea and dizziness.

      The most common adverse events resulting in discontinuation of patients following Cambia dosing in controlled clinical trials were urticaria (0.2%) and flushing (0.2%).

Clinical Studies Experience With Cambia

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

      The safety of a single dose of Cambia was evaluated in 2 placebo-controlled trials with a total of 634 migraine patients treated with Cambia for a single migraine headache. Following treatment with diclofenac potassium (either Cambia or diclofenac potassium immediate-release tablets [as a control]), 5 subjects (0.8%) withdrew from the studies; following placebo exposure, 1 subject (0.2%) withdrew.  No withdrawals were due to a serious reaction.

      The most common adverse reactions (i.e., that occurred in 1% or more of Cambia-treated patients) and more frequent with Cambia than with placebo were nausea and dizziness (see Table 1).

Table 1: Treatment-Related Adverse Reactions With Incidence >1% and Greater Than Placebo in Studies 1 and 2 Combined

Disorder       Event	Cambia N=634	Placebo N=646
Gastrointestinal       Nausea	3%	2%
Nervous System       Dizziness	1%	0.5%

 Adverse Reactions Reported With Diclofenac and Other NSAIDs

      In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are:

GI reactions (including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers [gastric/duodenal], and vomiting), abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus.

     

      Additional adverse reactions reported in patients taking  NSAIDs include occasionally:

Body as a Whole:   Fever, infection, sepsis

Cardiovascular System:   Congestive heart failure, hypertension, tachycardia, syncope

Digestive System:   Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and Lymphatic System: Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and Nutritional:   Weight changes

Nervous System:   Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory System:   Asthma, dyspnea

Skin and Appendages:   Alopecia, photosensitivity, sweating increased

Special Senses:   Blurred vision

Urogenital System:   Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

     

      Other adverse reactions in patients taking  NSAIDs, which occur rarely , are:

Body as a Whole: Anaphylactic reactions, appetite changes, death

Cardiovascular System: Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

Digestive System: Colitis, eructation, liver failure, pancreatitis

Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

Metabolic and Nutritional: Hyperglycemia

Nervous System: Convulsions, coma, hallucinations, meningitis

Respiratory System: Respiratory depression, pneumonia

Skin and Appendages: Angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria

Special Senses: Conjunctivitis, hearing impairment 

      DRUG INTERACTIONS

 Aspirin

      When administered with aspirin, diclofenac potassium’s protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Cambia and aspirin is not generally recommended because of the potential of increased adverse effects.

Anticoagulants

      The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that with use of either drug alone.

ACE Inhibitors

      NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking Cambia concomitantly with ACE inhibitors.

Diuretics

      Clinical studies, as well as post-marketing observations, have shown that diclofenac potassium can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe patients closely for signs of renal failure as well as to assure diuretic efficacy [see Warnings and Precautions (5.6)].

Lithium

      NSAIDs have produced elevations of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. When Cambia and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.

Methotrexate

      NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.

Cyclosporine

      Cambia, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Cambia may increase cyclosporine's nephrotoxicity. Use caution when Cambia is administered concomitantly with cyclosporine.

Inhibitors of Cytochrome P450 2C9

      Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co-administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [see Clinical Pharmacology (12.3)].

      USE IN SPECIFIC POPULATIONS      

Pregnancy

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

      Starting at 30 weeks gestation, Cambia, and other NSAIDS, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see Warnings and Precautions (5.9)]. There are no adequate and well controlled studies in pregnant women.

      Prior to 30 weeks gestation, Cambia should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

      Reproductive studies have been performed in mice given diclofenac sodium (up to 20 mg/kg/day, 2 times the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m2 basis), and in rats and rabbits given diclofenac sodium (up to 10 mg/kg/day; 2 [rats] and 4 [rabbits] times the RHD on a mg/m2 basis) and have revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.

Labor and Delivery 

      The effects of Cambia on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival.

 Nursing Mothers

      It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cambia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

      Safety and effectiveness in pediatric patients have not been established.

 Geriatric Use

      Clinical studies of Cambia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

      Elderly patients are at increased risk for serious GI adverse events.

      Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using Cambia in the elderly.

Hepatic Impairment

      Because hepatic metabolism accounts for almost 100% of diclofenac elimination, patients with hepatic impairment should be considered for treatment with Cambia only if the benefits outweigh the risks. There is insufficient information available to support dosing recommendations for Cambia in patients with hepatic insufficiency. [see Clinical Pharmacology (12.3)].

Renal Impairment

      No information is available from controlled clinical studies regarding the use of Cambia in patients with advanced renal disease. Therefore, treatment with Cambia is not recommended in patients with advanced renal disease. If Cambia therapy must be initiated, close monitoring of the patient's renal function is advisable.

      OVERDOSAGE

      Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

      Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

      DESCRIPTION

      Cambia  (Diclofenac Potassium for Oral Solution) is a benzeneacetic acid derivative NSAID. Cambia is available as a buffered soluble powder, designed to be mixed with water prior to oral administration.

      Cambia is a white to off-white, buffered, flavored powder for oral solution packaged in individual unit dose packets [see How Supplied/Storage and Handling (16)].  

      The chemical name for diclofenac potassium is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid monopotassium salt. The molecular weight of diclofenac potassium is 334.25. Its molecular formula is C14H10Cl2NKO2, and it has the following structural formula:

            

      The inactive ingredients in Cambia include: aspartame (equivalent to 25 mg phenylalanine), flavoring agents (anise and mint), glycerol behenate, mannitol, potassium bicarbonate, and saccharin sodium.

      CLINICAL PHARMACOLOGY

Mechanism of Action

Cambia is a non-steroidal anti-inflammatory drug (NSAID). The mechanism of action of Cambia, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.            

Pharmacokinetics

      Absorption: Diclofenac is 100% absorbed after oral administration compared to intravenous administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. In fasting volunteers, measurable plasma levels were observed within 5 minutes of dosing with Cambia. Peak plasma levels were achieved at approximately 0.25 hour in fasting normal volunteers, with a range of 0.17 to 0.67 hours. High fat food had no significant effect on the extent of diclofenac absorption, but there was a reduction in peak plasma levels of approximately 70% after a high fat meal. Decreased Cmax may be associated to decreased effectiveness.

      Distribution: The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg.

      Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses.

      Metabolism: Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxydiclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. In patients with renal impairment, peak concentrations of metabolites 4'-hydroxy-and 5- hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

      Excretion: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.

      Special Populations: 

Race: There are no pharmacokinetic differences due to race. 

Hepatic Impairment: The liver metabolizes almost 100% of diclofenac; there is insufficient information available to support dosing recommendations for Cambia in patients with hepatic insufficiency (5.3, 8.6)

Renal Impairment: In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.

      NON-CLINICAL STUDIES

Carcinogenesis, Mutagenesis, Impairment of Fertility

      Long term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m2] basis) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid-dose treated (0.5 mg/kg/day or 3 mg/m2/day ) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (less than the RHD on a mg/m2 basis) in males and 1 m/kg/day (less than the RHD on a mg/m2 basis) in females did not reveal any oncogenic potential.

      Diclofenac sodium was not genotoxic in in vitro (reverse mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including dominant lethal and male germinal epithelial chromosomal aberration in Chinese hamster) assays.

      Diclofenac sodium administered to male and female rats at 4 mg/kg/day (less than the RHD on a mg/m2 basis) did not affect fertility.

     

      CLINICAL STUDIES

      The efficacy of Cambia in the acute treatment of migraine headache was demonstrated in two randomized, double-blind, placebo-controlled trials.

      Patients enrolled in these two trials were predominantly female (85%) and white (86%), with a mean age of 40 years (range: 18 to 65). Patients were instructed to treat a migraine of moderate to severe pain with 1 dose of study medication. Patients evaluated their headache pain 2 hours later. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. In addition, the proportion of patients who were “sustained pain free”, defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours post-dose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours post-dose, was also evaluated. In these studies, the percentage of patients achieving pain freedom 2 hours after treatment and sustained pain freedom from 2 to 24 hours post-dose was significantly greater in patients who received Cambia compared with those who received placebo (see Table 2). The percentage of patients achieving pain relief 2 hours after treatment (defined as a reduction in headache severity from moderate or severe pain to mild or no pain) was also significantly greater in patients who received Cambia compared with those who received placebo (see Table 2).

     

Table 2: Percentage of Patients With 2-Hour Pain Freedom, Sustained Pain Freedom 2-24 Hours, and 2-Hour Pain Relief Following Treatment

Study 1	Cambia (n=265)	Placebo (n=257)
2-Hour Pain Free	24%	13%
2-24h Sustained Pain Free	22%	10%
2-Hour Pain Relief	48%	27%
Study 2	Cambia (n=343)	Placebo (n=347)
2-Hour Pain Free	25%	10%
2-24h Sustained Pain Free	19%	7%
2-Hour Pain Relief	65%	41%

      The estimated probability of achieving migraine headache pain freedom within 2 hours following treatment with Cambia is shown in Figure 1.

Figure 1. Percentage of Patients With Initial Headache Pain Freedom Within 2 Hours

There was a decreased incidence of nausea, photophobia and phonophobia following administration of Cambia, compared to placebo. The efficacy and safety of Cambia was unaffected by age or gender of the patient.

 

      HOW SUPPLIED/STORAGE AND HANDLING

      Cambia™ 50 mg (Diclofenac Potassium for Oral Solution) is supplied as one or more sets of three perforated co-joined individual dose packets. Each individual packet is designed to deliver a dose of 50 mg diclofenac potassium when mixed in water.

      Cambia is a white to off-white, buffered, flavored powder for oral solution packaged in individual unit dose packets.

Individual Cambia™ Packets - NDC 50192-113-01

Boxes of three (3) Cambia™ Packets – NDC 50192-113-03

Boxes of nine (9) Cambia™ Packets - NDC 50192-113-09

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

Manufactured by:

MIPHARM S.p.A.

Via Bernardo Quaranta, 12

20141 Milan, Italy

Manufactured for:

Nautilus Neurosciences, Inc.

135 Rte. 202/206 

Bedminster, NJ 08921

United States of America

Manufactured and Distributed Under License from APR Applied Pharma Research SA, Balerna Switzerland

Patient Counseling Information

      Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using Cambia [see Medication Guide (17.9)].

Cardiovascular Effects

      Cambia, like other NSAIDS, may cause serious CV events, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.1)].

Gastrointestinal Effects

      Cambia, like other NSAIDS, can cause GI discomfort and more serious GI adverse events such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, advise patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.2)].

Hepatotoxicity

      Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms). Instruct patients to stop therapy with Cambia and seek immediate medical therapy if any of these occur [see Warnings and Precautions (5.3)].

Weight Gain and Edema

      Advise patients to promptly report to their physicians signs or symptoms of unexplained weight gain or edema during treatment with Cambia [see Warnings and Precautions (5.5)].

Anaphylactoid Reactions

      Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Warnings and Precautions (5.7)].

Adverse Skin Reactions

      Cambia, like other NSAIDS, can cause serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrosis (TEN), which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop Cambia immediately if they develop any type of rash and to contact their physicians as soon as possible [see Warnings and Precautions (5.8)].

Effects During Pregnancy

      Starting at 30 weeks gestation, Cambia and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see Use in Specific Populations (8.1)].

Phenylketonurics

      Cambia packets contain aspartame equivalent to phenylalanine 25 mg per packet.

 FDA-Approved Medication Guide

      Upon dispensing to a patient please ensure the patient receives the attached Medication Guide.

MEDICATION GUIDE

Cambia (Cam-bē-ə or Cam-bē-a) 

(diclofenac potassium for oral solution)

Read the Patient Information that comes with Cambia before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

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

Cambia, which contains diclofenac, (a non-steroidal anti-inflammatory drug or NSAID), may increase your chance of a heart attack or stroke that can lead to death. This chance is higher:

• with longer use of NSAID medicines
  


• in people who have heart disease

NSAID medicines, such as Cambia, should never be used right before or after a heart surgery called a “coronary artery bypass graft” (CABG).

NSAID medicines, such as Cambia, can cause ulcers and bleeding in your stomach and intestines at any time during treatment.

Ulcers and bleeding:

• can happen without warning symptoms
  


• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• the use of medicines called steroid hormones (corticosteroids) and blood thinners (anticoagulants)
  


• longer or regular use
  


• smoking
  


• drinking alcohol
  


• older age
  


• having poor health

Cambia should only be used:

• exactly as prescribed
  


• at the lowest dose possible for your treatment
  


• for the shortest time needed

What is Cambia?

Cambia is a prescription medicine used to treat migraine attacks in adults. It does not prevent or lessen the number of migraines you have, and it is not for other types of headaches. Cambia contains diclofenac potassium (a Non-Steroidal Anti-Inflammatory Drug or NSAID).

How should I take Cambia?

Take Cambia exactly as your healthcare provider tells you to take it.

Take 1 dose of Cambia to treat your migraine headache:

• remove one single dose packet from a set of three packets
  


• open packet only when you are ready to use it
  


• empty contents of packet into 1 to 2 ounces (2 to 4 tablespoons) of water
  


• mix well and drink the water and powder mixture
  


• throw away empty packet in a safe place and out of the reach of children
  


• taking Cambia with food may cause a reduction in effectiveness compared to taking Cambia on an empty stomach
  


• do not take more Cambia than directed by your healthcare provider. In case of overdose, get medical help or contact a Poison Control Center right away

Who should not take Cambia?

Do not take Cambia:

• right before or after heart bypass surgery. See “What is the most important information I should know about Cambia?”
  


• if you have or have had an asthma attack, hives, or other allergic reaction with aspirin, diclofenac, or any other NSAID medicine

Before you take Cambia, tell your healthcare provider about all your medical conditions, including if you:

• have a history of stomach ulcer or bleeding in your stomach or intestines
  


• have kidney or liver problems
  


• have any allergies to any medicines
  


• have chest pain, shortness of breath, irregular heartbeats
  


• are pregnant, think you might be pregnant, or are trying to become pregnant. Cambia should not be used by pregnant women, especially during the last 3 months of pregnancy unless directed by your healthcare provider to do so. Cambia may cause problems in your unborn child or complications during your delivery
  


• are breastfeeding or plan to breastfeed. It is not known if Cambia passes into your breast milk. You and your doctor should decide if you will take Cambia or breastfeed. You should not do both
  


• have a headache that is different from your usual migraine

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.  

Cambia and other medicines may affect each other, causing side effects. Cambia may affect the way other medicines work, and other medicines may affect how Cambia works.

Especially tell your doctor if you take:

• aspirin
  


• any anticoagulant medicines (warfarin, Coumadin, Jantoven)

Know the medicines you take. Keep a list of your medicines and show it to your doctor and ph

S-T Forte 2

Generic Name: chlorpheniramine and hydrocodone (KLOR fen IR a meen and HYE droe KOE done)

Brand Names: HyTan, Novasus, S-T Forte 2, TussiCaps, Tussionex PennKinetic

What is S-T Forte 2 (chlorpheniramine and hydrocodone)?

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Hydrocodone is a narcotic cough suppressant.

The combination of chlorpheniramine and hydrocodone is used to treat runny or stuffy nose, sneezing, and cough caused by the common cold or flu.

Chlorpheniramine and hydrocodone may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about S-T Forte 2 (chlorpheniramine and hydrocodone)?

Do not take this medication more often than prescribed. An overdose of chlorpheniramine and hydrocodone can cause life-threatening side effects. To be sure you get the correct dose, measure this medicine carefully with a marked measuring spoon or syringe, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Before you take chlorpheniramine and hydrocodone, tell your doctor if you have asthma or another breathing disorder, a history of head injury or brain tumor, stomach or intestinal problems, liver or kidney disease, glaucoma, urination problems or an enlarged prostate, Addison's disease, or underactive thyroid.

Chlorpheniramine and hydrocodone can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol while using chlorpheniramine and hydrocodone. Alcohol may increase drowsiness and dizziness. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it. Do not give this medicine to a child younger than 6 years old.

What should I discuss with my healthcare provider before taking S-T Forte 2 (chlorpheniramine and hydrocodone)?

You should not take this medication if you are allergic to chlorpheniramine or hydrocodone.

Before taking chlorpheniramine and hydrocodone, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  asthma or other breathing disorder;

  
  


• 
  

  a history of head injury or brain tumor;

  
  


• 
  

  stomach or intestinal problems;

  
  


• liver or kidney disease;


• 
  

  glaucoma;

  
  


• 
  

  urination problems or an enlarged prostate;

  
  


• 
  

  Addison's disease; or

  
  


• 
  

  underactive thyroid.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

FDA pregnancy category C. Chlorpheniramine and hydrocodone may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether chlorpheniramine and hydrocodone passes into breast milk or if it could harm a nursing baby. Do not take this medication without telling your doctor if you are breast-feeding a baby. Older adults may be more likely to have side effects from this medicine. Do not give chlorpheniramine and hydrocodone to a child younger than 6 years old.

How should I take S-T Forte 2 (chlorpheniramine and hydrocodone)?

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

Do not take this medication more often than you doctor has prescribed. An overdose of chlorpheniramine and hydrocodone can cause life-threatening side effects. Shake the oral solution (liquid) well just before you measure a dose. To be sure you get the correct dose, measure the liquid carefully with a marked measuring spoon or syringe, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one. Do not mix this medicine with any other liquid before taking it. Chlorpheniramine and hydrocodone can be taken with food if it upsets your stomach. Store chlorpheniramine and hydrocodone at room temperature away from moisture and heat. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of chlorpheniramine and hydrocodone can be fatal, especially to a child.

Overdose symptoms may include dry mouth, cold and clammy skin, flushing, large pupils, nausea, vomiting, severe dizziness or drowsiness, seizure (convulsions), shallow breathing, slow heart rate, blue colored skin, feeling light-headed, or fainting.

What should I avoid while taking S-T Forte 2 (chlorpheniramine and hydrocodone)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol while using chlorpheniramine and hydrocodone. Alcohol may increase drowsiness and dizziness.

S-T Forte 2 (chlorpheniramine and hydrocodone) 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. Call your doctor at once if you have any of these serious side effects:

• 
  

  weak or shallow breathing;

  
  


• 
  

  chest tightness;

  
  


• 
  

  painful urination;

  
  


• 
  

  urinating less than usual or not at all; or

  
  


• 
  

  confusion, hallucinations, or unusual behavior.

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness, trouble concentrating;

  
  


• 
  

  mood changes, anxiety;

  
  


• 
  

  blurred vision;

  
  


• 
  

  constipation, nausea, vomiting, loss of appetite;

  
  


• 
  

  dry mouth or throat;

  
  


• 
  

  sweating; or

  
  


• 
  

  mild itching or skin rash.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect S-T Forte 2 (chlorpheniramine and hydrocodone)?

Narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine and hydrocodone. Tell your doctor if you regularly use any of these medicines, or any other cold or allergy medicine.

Tell your doctor about all other medications you use, especially:

• 
  

  atropine (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm-Scop);

  
  


• 
  

  bronchodilators such as ipratroprium (Atrovent) or tiotropium (Spiriva);

  
  


• 
  

  glycopyrrolate (Robinul);

  
  


• 
  

  mepenzolate (Cantil);

  
  


• 
  

  bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);

  
  


• 
  

  irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), or propantheline (Pro-Banthine); or

  
  


• 
  

  an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate).

  
  

This list is not complete and there may be other drugs that can interact with chlorpheniramine and hydrocodone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More S-T Forte 2 resources

• S-T Forte 2 Side Effects (in more detail)
• S-T Forte 2 Use in Pregnancy & Breastfeeding
• S-T Forte 2 Drug Interactions
• S-T Forte 2 Support Group
• 0 Reviews for S-T Forte 2 - Add your own review/rating

• S-T Forte 2 Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• TussiCaps Prescribing Information (FDA)


• TussiCaps Extended Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Tussionex Pennkinetic Extended-Release Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

Compare S-T Forte 2 with other medications

• Cold Symptoms
• Cough

Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine and hydrocodone.

See also: S-T Forte 2 side effects (in more detail)

Arrestin

Generic Name: trimethobenzamide (Intramuscular route)

trye-meth-oh-BENZ-a-mide

Commonly used brand name(s)

In the U.S.

• Arrestin


• Benzacot


• Stemetic


• Ticon


• Tigan


• Tribenzagan

Available Dosage Forms:

• Solution

Therapeutic Class: Antiemetic

Pharmacologic Class: Anticholinergic

Uses For Arrestin

Trimethobenzamide is used to treat nausea and vomiting .

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

Before Using Arrestin

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

No information is available on the relationship of age to the effects of intramuscular trimethobenzamide in the pediatric population. However, because of this medication's toxicity, use in children is contraindicated. Intramuscular trimethobenzamide should never be used in children .

Geriatric

No information is available on whether the risk of trimethobenzamide-induced adverse effects is increased in the elderly. However, because of this medication's toxicity, it should be used with caution, after less toxic alternatives have been considered and/or found ineffective. Recommended doses should not be exceeded, and the patient should be carefully monitored during therapy .

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 receiving 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 not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Metoclopramide

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.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Dehydration or


• Electrolyte imbalance (high or low levels of minerals in the blood) or


• High fever or


• Intestinal infection, severe—May cause side effects to become worse .

Proper Use of trimethobenzamide

This section provides information on the proper use of a number of products that contain trimethobenzamide. It may not be specific to Arrestin. Please read with care.

Trimethobenzamide is only used to relieve or prevent nausea and vomiting. A nurse or other trained health professional will give you this medicine. This medicine is given as a shot into one of your muscles .

Your doctor may only give you a few doses of this medicine until your condition improves, and then may switch you to an oral medicine that works the same way. If you have any concerns about this, talk to your doctor .

Precautions While Using Arrestin

Trimethobenzamide 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 medicines for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicines; prescription pain medicines or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of these medicines while you are using trimethobenzamide .

This medicine may cause some people to become dizzy, lightheaded, drowsy, 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 .

Arrestin 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:

Rare

• Body spasm, with head and heels bent backward and body bowed forward


• convulsions (seizures)


• depression


• shakiness or tremors


• skin rash


• sore throat or fever


• unusual tiredness


• vomiting (severe or continuing)


• yellow eyes or skin

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

• Drowsiness

Less common

• Blurred vision


• diarrhea


• dizziness


• headache


• muscle cramps

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: Arrestin 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 Arrestin resources

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

Compare Arrestin with other medications

• Nausea/Vomiting

Fluor-A-Day Drops

Pronunciation: SOE-dee-um FLOOR-ide
Generic Name: Sodium Fluoride
Brand Name: Examples include Fluor-A-Day, Fluoritab, and Kardium

Fluor-A-Day Drops are used for:

Preventing cavities in children older than 6 months of age when the amount of fluoride in the water supply is too low.

Fluor-A-Day Drops are a mineral. It works by strengthening the teeth and decreasing the effects of acid and bacteria on the teeth.

Do NOT use Fluor-A-Day Drops if:

• you are allergic to any ingredient in Fluor-A-Day Drops


• your drinking water has a fluoride content greater than 0.6 parts per million (ppm)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Fluor-A-Day Drops:

Some medical conditions may interact with Fluor-A-Day Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have joint pain, kidney problems, softening of your bones (osteomalacia, rickets), or stomach or intestinal ulcers

Some MEDICINES MAY INTERACT with Fluor-A-Day Drops. However, no specific interactions with Fluor-A-Day Drops are known at this time.

Ask your health care provider if Fluor-A-Day Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Fluor-A-Day Drops:

Use Fluor-A-Day Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Fluor-A-Day Drops by mouth with or without food. Do not eat or drink dairy products within 1 hour before or 2 hours after taking Fluor-A-Day Drops.


• Do not take an antacid that has aluminum, calcium, or magnesium in it for several hours after you take Fluor-A-Day Drops.


• Use the dropper that comes with Fluor-A-Day Drops to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose.


• Certain brands of Fluor-A-Day Drops should be mixed in juice or water before you take it. Contact your doctor or pharmacist if you are unsure if you should mix Fluor-A-Day Drops in juice or water.


• Certain brands of Fluor-A-Day Drops should be taken at bedtime after you brush your teeth unless your doctor tells you otherwise. Contact your doctor or pharmacist if you are unsure when to take Fluor-A-Day Drops.


• If you miss a dose of Fluor-A-Day Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Fluor-A-Day Drops.

Important safety information:

• Do NOT use more than the dose recommended by your doctor or dentist.


• Notify your dentist if your teeth become spotted or stained.


• Fluor-A-Day Drops should not be used in CHILDREN younger than 6 months old; safety and effectiveness in these children have not been confirmed.


• Caution is advised when using Fluor-A-Day Drops in CHILDREN younger than 6 years of age. The appropriate dose of Fluor-A-Day Drops depends on the child's age and the amount of fluoride in the drinking water. Talk with your doctor if you have questions about the appropriate dose for your child or the amount of fluoride in your drinking water.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while using Fluor-A-Day Drops, contact your doctor. You will need to discuss the benefits and risks of using Fluor-A-Day Drops while you are pregnant. It is not known if Fluor-A-Day Drops are found in breast milk. If you are or will be breast-feeding while you are using Fluor-A-Day Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Fluor-A-Day Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with Fluor-A-Day Drops. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Fluor-A-Day side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include bloody vomit or vomit that looks like coffee grounds; diarrhea; fast or irregular heartbeat; increased drooling; muscle weakness; nausea; seizures; slow or shallow breathing; sore tongue; stomach pain or cramping; tremor; vomiting.

Proper storage of Fluor-A-Day Drops:

Store Fluor-A-Day Drops at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Fluor-A-Day Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Fluor-A-Day Drops, please talk with your doctor, pharmacist, or other health care provider.


• Fluor-A-Day Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Fluor-A-Day Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Fluor-A-Day resources

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

Compare Fluor-A-Day with other medications

• Prevention of Dental Caries