Kivexa film-coated tablets

1. Name Of The Medicinal Product

Kivexa® 600 mg/300 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 600 mg of abacavir (as sulfate) and 300 mg lamivudine.

Excipient: sunset yellow (E110) 1.7 mg per tablet

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

Orange, film-coated, modified capsule shaped tablets, debossed with GS FC2 on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Kivexa is a fixed-dose combination of two nucleoside analogues (abacavir and lamivudine). It is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age (see sections 4.4 and 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Kivexa therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing (see section 4.4 and 4.8).

4.2 Posology And Method Of Administration

Posology

Therapy should be prescribed by a physician experienced in the management of HIV infection.

The recommended dose of Kivexa in adults and adolescents is one tablet once daily.

Kivexa should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.

Kivexa can be taken with or without food.

Kivexa is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations of abacavir or lamivudine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the individual product information for these medicinal products.

Renal impairment: Kivexa is not recommended for use in patients with a creatinine clearance < 50 ml/min (see section 5.2).

Hepatic impairment: No data are available in patients with moderate hepatic impairment, therefore the use of Kivexa is not recommended unless judged necessary. In patients with mild and moderate hepatic impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see sections 4.4 and 5.2). Kivexa is contraindicated in patients with severe hepatic impairment (see section 4.3).

Elderly: No pharmacokinetic data are currently available in patients over 65 years of age. Special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.

Paediatric population: Kivexa is not recommended for the treatment of children less than 12 years of age as the necessary dose adjustment cannot be made.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients. See BOXED INFORMATION ON ABACAVIR HYPERSENSITIVITY REACTIONS in section 4.4 and section 4.8.

Patients with severe hepatic impairment.

4.4 Special Warnings And Precautions For Use

The special warnings and precautions relevant to abacavir and lamivudine are included in this section. There are no additional precautions and warnings relevant to Kivexa.

Hypersensitivity reaction (see also section 4.8 ) In a clinical study , 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir developed a hypersensitivity reaction. Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. Based on the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding abacavir in patients with this allele significantly reduced the incidence of abacavir hypersensitivity reactions. In populations similar to that enrolled in the PREDICT-1 study, it is estimated that 48% to 61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701 allele. These results are consistent with those of prior retrospective studies. As a consequence, before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Kivexa therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available based on the treatment history and resistance testing (see section 4.1). In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision-making. It is noteworthy that among patients with a clinically suspected hypersensitivity reaction, a proportion did not carry HLA-B*5701. Therefore, even in the absence of HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction. Skin patch testing was used as a research tool for the PREDICT-1 study but has no utility in the clinical management of patients and therefore should not be used in the clinical setting. • Clinical Description Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome. Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat, cough, and abnormal chest x-ray findings (predominantly infiltrates, which can be localised), gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia). The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life- threatening. These symptoms usually resolve upon discontinuation of abacavir. • Clinical Management Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with abacavir, with consultation every two weeks. Regardless of their HLA-B*5701 status, patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue Kivexa immediately. Kivexa, or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir), MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death. To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Kivexa must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products). Special care is needed for those patients simultaneously starting treatment with Kivexa and other medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions. • Management after an interruption of Kivexa therapy Regardless of a patient's HLA-B*5701 status, if therapy with Kivexa has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, Kivexa or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir) must not be restarted. Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction (i.e. patients previously considered to be abacavir tolerant). In both cases if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available. Screening for carriage of the HLA B*5701 allele is recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. Re-initiation of abacavir in such patients who test positive for the HLA B*5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision. • Essential patient information Prescribers must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction: - Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death and that the risk of a hypersensitivity reaction is increased if they are HLA-B*5701 positive. - Patients must also be informed that a HLA-B*5701 negative patient can also experience an abacavir hypersensitivity reaction. Therefore, ANY patient who develops signs or symptoms consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT THEIR DOCTOR IMMEDIATELY. - - Patients who are hypersensitive to abacavir should be reminded that they must never take Kivexa or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir) again, regardless of their HLA-B*5701 status. . - In order to avoid restarting abacavir, patients who have experienced a hypersensitivity reaction should dispose of their remaining Kivexa tablets in their possession in accordance with the local requirements, and ask their doctor or pharmacist for advice. - Patients who have stopped Kivexa for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting. - Patients should be advised of the importance of taking Kivexa regularly. - Each patient should be reminded to read the Package Leaflet included in the Kivexa package. - They should be reminded of the importance of removing the Alert Card included in the package, and keeping it with them at all times. Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.

Lipodystrophy: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Pancreatitis: pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.

Risk of virological failure:

- Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir disoproxil fumarate as a once daily regimen.

- The risk of virological failure with Kivexa might be higher than with other therapeutic options (see section 5.1).

Liver disease: The safety and efficacy of Kivexa has not been established in patients with significant underlying liver disorders. Kivexa is contraindicated in patients with severe hepatic impairment (see section 4.3).

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Patients with chronic hepatitis B or C: Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection can be found in the Summary of Product Characteristics of products such as Zeffix.

If Kivexa is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see the Summary of Product Characteristics for a product such as Zeffix).

As abacavir and ribavirin share the same phosphorylation pathways, a possible intracellular interaction between these drugs has been postulated, which could lead to a reduction in intracellular phosphorylated metabolites of ribavirin and, as a possible consequence, a reduced chance of sustained virological response (SVR) for Hepatitis C (HCV) in HCV co-infected patients treated with pegylated interferon plus RBV. Conflicting clinical findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when both drugs are co-administered. (see section 4.5).

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome: in HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections: patients should be advised that Kivexa or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Transmission of HIV: patients should be advised that current antiretroviral therapy, including Kivexa, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Myocardial infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Kivexa, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Kivexa should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

Excipients: Kivexa contains the azo colouring agent sunset yellow, which may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Kivexa contains abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Kivexa. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine.

Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase; co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.

Abacavir and lamivudine are not significantly metabolised by cytochrome P₄₅₀ enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P₄₅₀ enzymes.

Interaction studies have only been performed in adults. The list below should not be considered exhaustive but is representative of the classes studied.

Drugs by Therapeutic Area	Interaction Geometric mean change (%) (Possible mechanism)	Recommendation concerning co-administration
ANTIRETROVIRAL MEDICINAL PRODUCTS
Didanosine /Abacavir	Interaction not studied.	No dosage adjustment necessary.
Didanosine/Lamivudine	Interaction not studied.
Zidovudine/Abacavir	Interaction not studied
Zidovudine/Lamivudine Zidovudine 300 mg single dose Lamivudine 150 mg single dose	Lamivudine: AUC ↔ Zidovudine : AUC ↔
ANTI-INFECTIVE PRODUCTS
Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Abacavir	Interaction not studied.	No Kivexa dosage adjustment necessary, unless patient has renal impairment (See Section 4.2). When concomitant administration with co-trimoxazole is warranted, patients should be monitored clinically. High doses of trimethoprim/ sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided.
Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Lamivudine (160mg/800mg once daily for 5 days/300mg single dose)	Lamivudine: AUC ↑40% Trimethoprim: AUC ↔ Sulfamethoxazole: AUC ↔ (organic cation transporter inhibition)
ANTIMYCOBACTERIALS
Rifampicin/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment.
Rifampicin/Lamivudine	Interaction not studied.
ANTICONVULSANTS
Phenobarbital/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment.
Phenobarbital/Lamivudine	Interaction not studied.
Phenytoin/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment. Monitor phenytoin concentrations.
Phenytoin/Lamivudine	Interaction not studied.
ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)
Ranitidine/Abacavir	Interaction not studied.	No dosage adjustment necessary.
Ranitidine/Lamivudine	Interaction not studied. Clinically significant interaction unlikely. Ranitidine eliminated only in part by renal organic cation transport system.
Cimetidine/Abacavir	Interaction not studied.	No dosage adjustment necessary.
Cimetidine/Lamivudine	Interaction not studied. Clinically significant interaction unlikely. Cimetidine eliminated only in part by renal organic cation transport system.
OPIOIDS
Methadone/Abacavir (40 to 90mg once daily for 14 days/600mg single dose, then 600mg twice daily for 14 days)	Abacavir: AUC ↔ Cmax Methadone: CL/F ↑22%	No Kivexa dosage adjustment necessary. Methadone dosage adjustment unlikely in majority of patients; occasionally methadone re-titration may be required.
Methadone/Lamivudine	Interaction not studied.
RETINOIDS
Retinoid compounds (e.g. isotretinoin)/Abacavir	Interaction not studied. Possible interaction given common pathway of elimination via alcohol dehydrogenase.	Insufficient data to recommend dosage adjustment.
Retinoid compounds (e.g. isotretinoin)/Lamivudine No drug interaction studies	Interaction not studied.
ANTIVIRALS
Ribavirin/Abacavir	Interaction not studied. Theoretical potential to reduce intracellular phosphorylated metabolites.	Caution should be exercised when both drugs are co-administered (see section 4.4).
MISCELLANEOUS
Ethanol/Abacavir (0.7 g/kg single dose/600mg single dose)	Abacavir: AUC ↑41% Ethanol: AUC ↔ (Inhibition of alcohol dehydrogenase)	No dosage adjustment necessary.
Ethanol/Lamivudine	Interaction not studied.

Abbreviations: ↑ = Increase;

4.6 Pregnancy And Lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. There are no data on the use of Kivexa in pregnancy. A moderate amount of data on pregnant women taking the individual actives abacavir and lamivudine in combination indicates no malformative toxicity (more than 400 outcomes from first trimester exposures). Concerning lamivudine, a large amount of data (more than 3000 outcomes from first trimester) indicates no malformative toxicity. Moderate amount of data (more than 600 outcomes from first trimester) indicates no malformative toxicity for abacavir. The malformative risk is unlikely in humans based on the mentioned moderate amount of data.

The active ingredients of Kivexa may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown.

For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal product such as Kivexa and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Breastfeeding

Lamivudine is excreted in human milk at similar concentrations to those found in serum. It is expected that abacavir will also be excreted into human milk, although this has not been confirmed. As a general rule it is recommended that mothers infected with HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Fertility

Studies in animals showed that neither abacavir nor lamivudine had any effect on fertility (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on ability to drive and use machines have been performed. The clinical status of the patient and the adverse reaction profile of Kivexa should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Undesirable Effects

The adverse reactions reported for Kivexa were consistent with the known safety profiles of abacavir and lamivudine when given as separate medicinal products. For many of these adverse reactions it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.

Abacavir hypersensitivity (see also section 4.4) In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir developed a hypersensitivity reaction. In clinical studies with abacavir 600 mg once daily the reported rate of hypersensitivity remained within the range recorded for abacavir 300 mg twice daily. Some hypersensitivity reactions were life-threatening and resulted in fatal outcome despite taking precautions. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.
Skin	Rash (usually maculopapular or urticarial)
Gastrointestinal tract	Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration
Respiratory tract	Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
Miscellaneous	Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis
Neurological/Psychiatry	Headache, paraesthesia
Haematological	Lymphopenia
Liver/pancreas	Elevated liver function tests, hepatitis, hepatic failure
Musculoskeletal	Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase
Urology	Elevated creatinine, renal failure
Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Close medical supervision is necessary during the first two months, with consultations every two weeks. It is likely that intermittent therapy may increase the risk of developing sensitisation and therefore occurrence of clinically significant hypersensitivity reactions. Consequently, patients should be advised of the importance of taking Kivexa regularly. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue Kivexa and must never be rechallenged with Kivexa, or any other medicinal product containing abacavir (Ziagen or Trizivir). To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, abacavir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products). Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction. In both cases, if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available. Each patient must be warned about this hypersensitivity reaction to abacavir.

Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If Kivexa has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart a medicinal product containing abacavir, this must be done in a setting where medical assistance is readily available (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

The adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000).

Body system	Abacavir	Lamivudine
Blood and lymphatic systems disorders		Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia Very rare: Pure red cell aplasia
Immune system disorders	Common: hypersensitivity
Metabolism and nutrition disorders	Comm

Alprazolam

Class: Benzodiazepines
VA Class: CN302
Chemical Name: 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Molecular Formula: C₁₇H₁₃ClN₄
CAS Number: 28981-97-7
Brands: Niravam, Xanax

Introduction

Benzodiazepine; anxiolytic.^{b c}

Uses for Alprazolam

Anxiety Disorders

Management of anxiety disorders or short-term relief of anxiety or anxiety associated with depressive symptoms.^{b c}

Panic Disorder

Management of panic disorder, with or without agoraphobia.

Cancer Chemotherapy-induced Nausea and Vomiting

Adjunct in the management of nausea and vomiting associated with emetogenic cancer chemotherapy†^b (including cisplatin); ^b currently not recommended as monotherapy.^b

May be useful in the management of anticipatory emesis†.^c

Alprazolam Dosage and Administration

General

• 
  

  Periodically reassess usefulness of the drug.

  
  


• 
  

  When discontinuing therapy or reducing daily dosage, reduce dosage gradually under close supervision. If significant withdrawal symptoms develop, reinstitute the previous dosage schedule; attempt a less-rapid schedule of dosage tapering only after stabilization. Some patients may be resistant to all discontinuance regimens.

  
  


• 
  

  The manufacturers recommend that dosage be decreased by ≤0.5 mg every 3 days; some patients may require slower reduction.

  
  


• 
  

  Some clinicians recommend decreasing the dosage by ≤0.25 mg every 3–7 days.^{107 108 109}

  
  

Administration

Oral Administration

Immediate-release Preparations

Administer conventional and orally disintegrating tablets and oral concentrate daily in divided doses.^c

Dilute oral concentrate in ≥30 mL of diluent (e.g., water, juice, carbonated or soda-like beverages) or mix with semisolid foods (e.g., applesauce, pudding) just prior to administration.^c

Remove orally disintegrating tablet from protective container with dry hands immediately prior to administration. Immediately place tablet on tongue, allow it to disintegrate (within a few seconds), then swallow with or without water. If a half tablet is used, discard the remaining portion because it may not remain stable.

Extended-release Tablets

Administer extended-release tablets daily as a single dose, preferably in the morning.

Swallow extended-release tablets whole; do not chew, crush, or break.

Patients with panic disorder may be switched from conventional tablets to extended-release tablets at the same total daily dosage. If the response is not sufficient, titrate dosage in a similar manner to initial therapy until an acceptable therapeutic response is achieved.

Dosage

Adults

Anxiety Disorders

Therapy with Conventional or Orally Disintegrating Tablets or Oral Concentrate

Oral

Initially, 0.25–0.5 mg 3 times daily.^c Increase dosage gradually at intervals of 3 or 4 days according to individual requirements and response; maximum dosage of 4 mg daily given in divided doses.^c

Panic Disorder

Therapy with Conventional or Orally Disintegrating Tablets

Oral

Dosages >4 mg daily have been required; dosage generally has averaged 5–6 mg daily but has ranged from 1–10 mg daily.

Initiate at low dosage; increase dosage gradually until an acceptable therapeutic response is achieved, intolerable adverse effects occur, or a maximum dosage of 10 mg daily is achieved.

Initially, 0.5 mg 3 times daily. Increase dosage as necessary at 3- or 4-day intervals in increments of ≤1 mg daily; slower titration to dosages ≥4 mg daily may be advisable so that full effects of a given dosage can be expressed.

Periodic reassessment and consideration of dosage reduction recommended in patients receiving dosages >4 mg daily.

To minimize risk of symptom emergence between doses, distribute doses evenly 3–4 times daily (while awake).

Therapy with Extended-release Tablets

Oral

Dosage of 3–6 mg daily recommended, but dosage has ranged from 1–10 mg daily.

Initiate at low dosage; increase dosage gradually until an acceptable therapeutic response is achieved, intolerable adverse effects occur, or a maximum dosage of 10 mg daily is achieved.

Initially, 0.5–1 mg daily. Increase dosage as necessary (based on response) at 3- or 4-day intervals in increments of ≤1 mg daily; slower titration may be advisable so that full effects of a given dosage can be expressed.

Prescribing Limits

Adults

Anxiety Disorders

Oral

Maximum 4 mg daily.^c

Panic Disorder

Oral

Maximum 10 mg daily.

Special Populations

Hepatic Impairment

Prolonged elimination. Use the smallest effective dosage.^c

Initially, 0.25 mg (as an immediate-release preparation) given 2 or 3 times daily or 0.5 mg (as extended-release tablets) once daily; adjust dosage according to individual tolerance and response.

Geriatric or Debilitated Patients

Possible increased sensitivity to benzodiazepines.^b Use the smallest effective dosage.^c

Initially, 0.25 mg (as an immediate-release preparation) given 2 or 3 times daily or 0.5 mg (as extended-release tablets) once daily; adjust dosage according to individual tolerance and response.^c

Cautions for Alprazolam

Contraindications

• 
  

  Known hypersensitivity to alprazolam or other benzodiazepines.^b

  
  


• 
  

  Concurrent ketoconazole, itraconazole, or delavirdine therapy. (See Specific Drugs and Foods under Interactions.)

  
  


• 
  

  Manufacturers state that alprazolam is contraindicated in patients with acute angle-closure glaucoma but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy;^b however, clinical rationale for this contraindication has been questioned.^b

  
  

Warnings/Precautions

Warnings

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance may result in seizures (including status epilepticus),^{102 103} delirium,^{102 104} or withdrawal symptoms.^{101 104}

Risk of seizures is greatest 24–72 hours after discontinuance.

Use of relatively higher dosages (e.g., those employed for panic disorder) may be associated with an increased frequency and severity of rebound and withdrawal symptoms.

Psychiatric Indications

Do not use in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.^b

Abuse Potential

Abuse potential similar to that of other benzodiazepines and related hypnotics.

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.^{b c}

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Specific Drugs and Foods under Interactions.)

Drug Interactions

Potential for marked increase in plasma alprazolam concentrations if used concomitantly with a CYP3A inhibitor. Avoid concomitant use of potent CYP3A inhibitors (e.g., delavirdine, itraconazole, ketoconazole); use of less potent CYP3A inhibitors requires caution and possible dosage reduction. (See Specific Drugs and Foods under Interactions.)

General Precautions

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.^b Prescribe and dispense drug in the smallest feasible quantity.^b

Mania

Episodes of mania and hypomania reported in patients with depression.

Respiratory Effects

Rare reports of deaths following initiation of therapy in patients with severe pulmonary disease.

Use with caution in patients with compromised respiratory function.^b

Renal Effects

Weak uricosuric effect; however, no reports of acute renal failure.

Specific Populations

Pregnancy

Category D.

Lactation

Benzodiazepines generally are distributed into milk; discontinue nursing or the drug.^b

Pediatric Use

Safety and efficacy not established in children <18 years of age.^c

Geriatric Use

Potential increased sensitivity (increased risk of oversedation and ataxia).^{b c} Initiate therapy at low dosage and adjust carefully.^{b c} (See Geriatric or Debilitated Patients under Dosage and Administration.)

Hepatic Impairment

Prolonged elimination. Use with caution;^{b c} use smallest effective dosage to avoid oversedation.^{b c} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution.^b

Obese Patients

Use with caution; prolonged elimination reported.

Common Adverse Effects

In patients with anxiety disorder: drowsiness, lightheadedness, depression, headache, dry mouth, constipation, diarrhea.

Conventional tablets in patients with panic disorder: drowsiness, fatigue/tiredness, impaired coordination, irritability, memory impairment, lightheadedness/dizziness, insomnia, headache, cognitive disorder, dysarthria, anxiety, abnormal involuntary movement, decreased libido, depression, confusional state, decreased salivation, constipation, nausea/vomiting, diarrhea, abdominal distress, nasal congestion, tachycardia, chest pain, blurred vision, sweating, rash, increased appetite, decreased appetite, weight gain, weight loss, micturition difficulties, menstrual disorders.

Extended-release tablets in patients with panic disorder: sedation, somnolence, memory impairment, dysarthria, fatigue, depression, dry mouth.

Interactions for Alprazolam

Metabolized by CYP3A.

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of alprazolam) with drugs that induce or inhibit CYP3A. Avoid concomitant use with potent CYP3A inhibitors. Caution advised if alprazolam is used concomitantly with less potent CYP3A inhibitors; alprazolam dosage adjustment may be indicated. (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Salivary Flow or Gastric pH

Possible pharmacokinetic interaction (decreased alprazolam absorption) with concomitant use of alprazolam orally disintegrating tablets and drugs that increase gastric pH or decrease salivary flow.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	Possible increase in plasma alprazolam concentrations	Use with caution
Antidepressants, SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline)	Fluoxetine or fluvoxamine: Increased plasma alprazolam concentrations Paroxetine: Possible interaction in vitro Sertraline: Possible interaction in vitro; no clinically important interaction in vivo	Fluvoxamine: Use with caution; consider reduction of alprazolam dosage Fluoxetine, paroxetine, or sertraline: Use with caution
Antidepressants, tricyclics (e.g., imipramine, desipramine)	Possible increase in plasma concentrations of antidepressantb	Clinical importance unknown
Antifungals, azoles (e.g., itraconazole, ketoconazole)	Increased plasma alprazolam concentrations	Concomitant use of itraconazole or ketoconazole is contraindicated; avoid concomitant use of other azole antifungals that are potent CYP3A inhibitors
Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine)	Possible increase in plasma alprazolam concentrations	Use with caution
Carbamazepine	Possible decrease in plasma alprazolam concentrations
Cigarette smoking	Decreased plasma alprazolam concentrationsb
Cimetidine	Increased plasma alprazolam concentrations	Use with caution; consider reduction of alprazolam dosage
CNS depressants (e.g., opiates or other analgesics, sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)	Additive CNS effectb	Use caution to avoid overdosageb
Cyclosporine	Possible increase in plasma alprazolam concentrations	Use with caution
Delavirdine	Potential for decreased alprazolam metabolism resulting in intense and prolonged sedation and respiratory depression	Concomitant use contraindicated
Digoxin	Digoxin toxicity reported in at least 1 patient	Monitor carefully and adjust digoxin dosage as necessary
Disulfiram	Possible decrease in alprazolam clearance	Reduce alprazolam dosage as necessary
Ergotamine	Possible increase in plasma alprazolam concentrations	Use with caution
Grapefruit juice	Possible increase in plasma alprazolam concentrations	Use with caution
HIV protease inhibitors (e.g., amprenavir, fosamprenavir, ritonavir, saquinavir)	Possible increase in plasma alprazolam concentrations	Clinical importance not determined; consider possible need for alprazolam dosage reduction
Isoniazid	Possible increase in plasma alprazolam concentrations	Use with caution
Macrolides (e.g., clarithromycin, erythromycin)	Possible increase in plasma alprazolam concentrations	Use with caution
Nefazodone	Increased plasma alprazolam concentrations	Use with caution; consider reduction of alprazolam dosage
Oral contraceptives	Increased plasma alprazolam concentrations	Use with caution
Propoxyphene	Increased plasma alprazolam concentrations	Use with caution
Warfarin	No effect on PT or plasma warfarin concentrations observed

Alprazolam Pharmacokinetics

Absorption

Bioavailability

Readily absorbed following oral administration as conventional or orally disintegrating tablets or oral solution, with peak plasma concentrations achieved within 1–2 hours.

When orally disintegrating tablets are taken with water, peak plasma concentrations occur 15 minutes sooner than when taken without water, but actual peak concentration and AUC are unaffected.

Rate of absorption of extended-release tablets is slower than that of conventional tablets, resulting in relatively constant plasma concentrations for 5–11 hours after a dose.

Absolute bioavailability of extended-release tablets is 90%; bioavailability is equivalent to that of conventional tablets.

Absorption rate for extended-release tablets is faster following nighttime versus morning administration.

Food

High-fat meal may alter the rate but not the extent of absorption of orally disintegrating or extended-release tablets.

Special Populations

In patients with conditions that increase gastric pH or cause dry mouth, absorption of orally disintegrating tablets may be slower or reduced.

Distribution

Extent

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier.^b

Benzodiazepines generally cross the placenta and distribute into milk; because of its similarity to other benzodiazepines, alprazolam is presumed to cross the placenta and to distribute into milk.^b

Plasma Protein Binding

Approximately 80%, primarily to albumin.

Elimination

Metabolism

Extensively metabolized in the liver by CYP3A4 to metabolites that are inactive or have lower potency than alprazolam.

Elimination Route

Alprazolam and metabolites are excreted primarily in urine.

Half-life

Approximately 11–12.5 hours for immediate-release preparations; approximately 11–16 hours for extended-release tablets.

Special Populations

In geriatric patients, obese patients, and those with alcoholic liver disease, half-life is increased to approximately 16, 22, and 20 hours, respectively.^b

In Asians, half-life is about 25% greater than that in Caucasians.

Stability

Storage

Oral

Conventional Tablets

20–25°C.

Orally Disintegrating Tablets

20–25°C (may be exposed to 15–30°C). Protect from moisture. If a half tablet is used, discard remaining portion because it may not remain stable. Discard cotton after opening the container and reseal container tightly after each opening to prevent introduction of moisture.

Extended-release Tablets

25°C (may be exposed to 15–30°C).

Solution (Concentrate)

Tight, light-resistant containers at 15–30°C.

ActionsActions

• 
  

  Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABA_A-receptor-chloride ionophore complex) that includes GABA_A receptors, high-affinity benzodiazepine receptors, and chloride channels.

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption. Importance of avoiding alcohol-containing beverages or products.

  
  


• 
  

  Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.

  
  


• 
  

  For patients taking alprazolam orally disintegrating tablets, importance of not removing tablets from the container until just prior to administration; importance of removing tablet from container with dry hands and placing tablet on tongue to dissolve and be swallowed with saliva or water. Importance of discarding any cotton included in the container and of resealing the container tightly after each opening to prevent introduction of moisture.

  
  


• 
  

  For patients taking one-half of an orally disintegrating tablet, importance of immediately discarding the unused portion because of possible instability.

  
  


• 
  

  Importance of not abruptly discontinuing therapy; consult clinician about discontinuing use.

  
  


• 
  

  Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  
  


• 
  

  Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.^b

  
  


• 
  

  Potential for severe emotional and physical dependence in some patients receiving increased dosages for the management of panic disorder. Discontinuance of the drug may be difficult, with increased risk of withdrawal symptoms, including seizures.

  
  


• 
  

  Importance of informing clinicians about any concomitant illnesses, particularly depression.

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.^c

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Alprazolam

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution, concentrate	1 mg/mL	Alprazolam Intensol (C-IV)	Roxane
	Tablets	0.25 mg*	Xanax (C-IV; scored)	Pfizer
		0.5 mg*	Xanax (C-IV; scored)	Pfizer
		1 mg*	Xanax (C-IV; scored)	Pfizer
		2 mg*	Xanax (C-IV; multi-scored)	Pfizer
	Tablets, extended-release	0.5 mg	Alprazolam Extended-Release Tablets (C-IV)	Mylan, Sandoz
			Xanax XR (C-IV)	Pfizer
		1 mg	Alprazolam Extended-Release Tablets (C-IV)	Mylan, Sandoz
			Xanax XR (C-IV)	Pfizer
		2 mg	Alprazolam Extended-Release Tablets (C-IV)	Mylan, Sandoz
			Xanax XR (C-IV)	Pfizer
		3 mg	Alprazolam Extended-Release Tablets (C-IV)	Mylan, Sandoz
			Xanax XR (C-IV)	Pfizer
	Tablets, orally disintegrating	0.25 mg	Niravam (C-IV; scored)	Schwarz
		0.5 mg	Niravam (C-IV; scored)	Schwarz
		1 mg	Niravam (C-IV; scored)	Schwarz
		2 mg	Niravam (C-IV; scored)	Schwarz

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

ALPRAZolam 0.25MG Tablets (GREENSTONE): 30/$11.99 or 90/$15.97

ALPRAZolam 0.5MG Tablets (GREENSTONE): 30/$11.99 or 60/$12.97

ALPRAZolam 1MG Tablets (GREENSTONE): 30/$12.99 or 60/$14.98

ALPRAZolam 2MG Tablets (GREENSTONE): 30/$14.99 or 60/$17.97

ALPRAZolam XR 0.5MG 24-hr Tablets (GREENSTONE): 30/$31.99 or 90/$71.97

ALPRAZolam XR 1MG 24-hr Tablets (GREENSTONE): 30/$69.99 or 90/$196.96

ALPRAZolam XR 2MG 24-hr Tablets (GREENSTONE): 30/$75.99 or 90/$219.97

ALPRAZolam XR 3MG 24-hr Tablets (GREENSTONE): 30/$109.98 or 90/$309.97

Niravam 0.25MG Dispersible Tablets (AZUR PHARMA): 30/$103.58 or 90/$274.17

Niravam 0.5MG Dispersible Tablets (AZUR PHARMA): 30/$136.99 or 90/$361.98

Niravam 1MG Dispersible Tablets (AZUR PHARMA): 30/$178 or 90/$490.96

Niravam 2MG Dispersible Tablets (AZUR PHARMA): 30/$255.9 or 90/$710.95

Xanax 0.25MG Tablets (PFIZER U.S.): 30/$53.99 or 90/$136.39

Xanax 0.5MG Tablets (PFIZER U.S.): 30/$61.59 or 90/$167.97

Xanax 1MG Tablets (PFIZER U.S.): 30/$76.54 or 90/$204.96

Xanax 2MG Tablets (PFIZER U.S.): 30/$124.64 or 90/$341.02

Xanax XR 0.5MG 24-hr Tablets (PFIZER U.S.): 30/$96.99 or 90/$268.96

Xanax XR 1MG 24-hr Tablets (PFIZER U.S.): 30/$116.99 or 90/$338.96

Xanax XR 2MG 24-hr Tablets (PFIZER U.S.): 30/$151.99 or 90/$435.97

Xanax XR 3MG 24-hr Tablets (PFIZER U.S.): 30/$216 or 90/$617.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

101. Noyes R Jr, Clancy J, Coryell WH et al. A withdrawal syndrome after abrupt discontinuance of alprazolam. Am J Psychiatry. 1985; 142:114-6. [IDIS 194746] [PubMed 2857066]

102. Levy AB. Delirium and seizures due to abrupt alprazolam withdrawal: case report. J Clin Psychiatry. 1984; 45:38-9. [IDIS 180244] [PubMed 6141159]

103. Breier A, Charney DS, Nelson JC. Seizures induced by abrupt discontinuance of alprazolam. Am J Psychiatry. 1984; 141:1606-7. [IDIS 193450] [PubMed 6150649]

104. Zipursky RB, Baker RW, Zimmer B. Alprazolam withdrawal delirium unresponsive to diazepam: case report. J Clin Psychiatry. 1985; 46:344-5. [IDIS 204423] [PubMed 2862137]

105. Greenblatt DJ, Shader RI, Abernathy DR. Current status of benzodiazepines (second of two parts). N Engl J Med. 1983; 309:410-6. [IDIS 174051] [PubMed 6135990]

107. Pecknold JC, Swinson RP, Kuch K et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Arch Gen Psychiatry. 1988; 45:429-36. [IDIS 241071] [PubMed 3282479]

108. Ayd FJ Jr. Problems associated with alprazolam therapy. Int Drug Ther Newsl. 1988; 23:29-31.

109. Ayd FJ Jr. Discontinuing alprazolam. Int Drug Ther Newsl. 1987; 22:27.

110. Anon. Choice of benzodiazepines. Med Lett Drugs Ther. 1988; 30:26-8. [PubMed 2893246]

111. Fyer AJ, Liebowitz MR, Gorman JM et al. Discontinuation of alprazolam treatment in panic patients. Am J Psychiatry. 1987; 144:303-8. [IDIS 226348] [PubMed 3826428]

b. AHFS drug information 2007. McEvoy GK, ed. Benzodiazepines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2508-18.

c. AHFS drug information 2007. McEvoy GK, ed. Alprazolam. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2518-9.

More Alprazolam resources

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

• Alprazolam Prescribing Information (FDA)


• Alprazolam MedFacts Consumer Leaflet (Wolters Kluwer)


• Alprazolam Professional Patient Advice (Wolters Kluwer)


• Niravam Prescribing Information (FDA)


• Niravam Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Xanax Prescribing Information (FDA)


• Xanax Consumer Overview


• Xanax XR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Xanax XR Consumer Overview


• Xanax XR Prescribing Information (FDA)


• alprazolam Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Alprazolam with other medications

• Anxiety
• Depression
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• Panic Disorder
• Tinnitus

WindSetlers

1. Name Of The Medicinal Product

WindSetlers

2. Qualitative And Quantitative Composition

Each Capsules contains Simeticone 100mg

Also contains sodium ethyl parahydroxybenzoate (E215) and sodium propyl hydroxybenzoate (E217)

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Soft gelatin capsules

4. Clinical Particulars

4.1 Therapeutic Indications

Anti-flatulent defoaming agent for the symptomatic relief of flatulence, wind pains, bloating, abdominal distension and other symptoms associated with intestinal gas.

4.2 Posology And Method Of Administration

Oral

Adults, the elderly and children:

One or two capsules taken 3 or 4 times daily or as required for relief.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

None stated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None reported.

4.6 Pregnancy And Lactation

As dimeticone is not absorbed, it is not anticipated that WindSetlers will have any adverse effects on pregnancy and lactation. However, as with all drugs, caution should be exercised in these conditions.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

As dimeticone is not absorbed from the gastro-intestinal tract, adverse effects attributable to the active ingredient would not be expected.

4.9 Overdose

No cases of overdose have been reported. Theoretically, constipation may occur. Treat with fluids and keep under observation.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

WindSetlers contain activated dimeticone, a chemically inert gastric defoaming agent which alters the elasticity of interfaces of mucous-embedded bubbles in the gastro-intestinal tract. The gas bubbles are thus broken or coalesced and in this form, the gas is more easily eliminated through belching or passing flatus.

5.2 Pharmacokinetic Properties

Activated dimeticone is not absorbed from the gastrointestinal tract and does not interfere with gastric secretion or absorption of nutrients. Following oral administration, it is excreted unchanged in the faeces.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule Shell:

Gelatin

Glycerin

Colour (E142)

Quinoline Yellow (E104)

Titanium Dioxide (E171)

Sodium Ethyl Parahydroxybenzoate (E215)

Sodium Propyl Parahydroxybenzoate (E217)

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years unopened.

6.4 Special Precautions For Storage

Store below 25°C in a dry place

6.5 Nature And Contents Of Container

25µ cold formed aluminium blister packs in cardboard cartons in packs of 8, 24 and 30 capsules or glass bottles of 24, 30 or 60 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Thornton & Ross Limited

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0095

9. Date Of First Authorisation/Renewal Of The Authorisation

1 March 2003

10. Date Of Revision Of The Text

16/10/2008

11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

Ihtamol

Ihtamol may be available in the countries listed below.

Ingredient matches for Ihtamol

Ichthammol

Ichthammol is reported as an ingredient of Ihtamol in the following countries:

• Turkey

International Drug Name Search

fosaprepitant Intravenous

fos-a-PRE-pi-tant dye-MEG-loo-meen

Commonly used brand name(s)

In the U.S.

• Emend

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antiemetic

Pharmacologic Class: Fosaprepitant

Uses For fosaprepitant

Fosaprepitant is used with other medicines to prevent nausea and vomiting caused by cancer treatment (chemotherapy). It acts in the brain to prevent nausea.

fosaprepitant is available only with your doctor's prescription.

Before Using fosaprepitant

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 fosaprepitant, the following should be considered:

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of fosaprepitant in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of fosaprepitant in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

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 fosaprepitant, 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 fosaprepitant 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.

• Astemizole


• Cisapride


• Pimozide


• Terfenadine

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

• Etoposide


• Ifosfamide


• Imatinib


• Irinotecan


• Paclitaxel


• Vinblastine


• Vincristine

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

• Alprazolam


• Desogestrel


• Dexamethasone


• Dienogest


• Diltiazem


• Drospirenone


• Estradiol Cypionate


• Estradiol Valerate


• Ethinyl Estradiol


• Ethynodiol Diacetate


• Etonogestrel


• Ketoconazole


• Levonorgestrel


• Medroxyprogesterone Acetate


• Mestranol


• Midazolam


• Norelgestromin


• Norethindrone


• Norgestimate


• Norgestrel


• Rifampin


• Tolbutamide


• Triazolam

Interactions with Food/Tobacco/Alcohol

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

Proper Use of fosaprepitant

A nurse or other trained health professional will give you fosaprepitant in a hospital or clinic. fosaprepitant is given through a needle placed in one of your veins.

fosaprepitant is usually given on the first day of your chemotherapy as part of a three-day regimen along with other medicines. Fosaprepitant is not for long-term use, but you may need to use fosaprepitant again if you have more chemotherapy in the future.

fosaprepitant comes with a patient information insert. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Precautions While Using fosaprepitant

It is very important that your doctor check your progress at regular visits to make sure fosaprepitant is working properly and to check for unwanted effects.

You should not receive fosaprepitant if you are also using cisapride (Propulsid®) or pimozide (Orap®). Fosaprepitant may cause serious or life-threatening problems if used together with these medicines.

fosaprepitant may cause serious allergic reactions. Tell your doctor or nurse right away if you have itching; hives; a rash; shortness of breath; trouble with breathing; trouble with swallowing; warmth or redness in your face, neck, arms, or upper chest; or any swelling of your hands, face, or mouth while you are receiving fosaprepitant.

If you are also taking a blood thinner called warfarin (Coumadin®, Jantoven®), your doctor will need to check your blood after using fosaprepitant.

Birth control pills may not work as well while you are using fosaprepitant. To keep from getting pregnant, use another form of birth control together with your pills during treatment and for one month after your last treatment. Other forms include condoms, diaphragms, and contraceptive foams or jellies.

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

fosaprepitant 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 or nurse immediately if any of the following side effects occur:

More common

• Black, tarry stools


• blurred vision


• chills


• confusion


• cough


• decreased urination


• difficult or labored breathing


• dizziness


• dry mouth


• fainting


• fever


• increase in heart rate


• lightheadedness


• lower back or side pain


• nervousness


• pain, swelling, or redness at the injection site


• painful or difficult urination


• pale skin


• pounding in the ears


• rapid breathing


• shortness of breath


• slow or fast heartbeat


• sore throat


• sunken eyes


• tenderness, swelling, warmth, or skin discoloration at the injection site


• thirst


• tightness in the chest


• ulcers, sores, or white spots in mouth


• unusual bleeding or bruising


• unusual tiredness or weakness


• wheezing


• wrinkled skin

Less common

• Hard lump at the injection site

Rare

• Blood in the urine


• changes in patterns and rhythms of speech


• changes in skin color


• chest pain or discomfort


• coma


• convulsions


• fast, slow, irregular, pounding, or racing heartbeat or pulse


• general feeling of discomfort or illness


• headache


• increased sweating


• increased thirst


• lightheadedness, dizziness, or fainting


• muscle pain or cramps


• nausea or vomiting


• pain, tenderness, or swelling of the foot or leg


• slurred speech


• swelling


• swelling of the face, ankles, or hands


• trouble with speaking


• troubled breathing with exertion


• wheezing

Incidence not known

• Difficulty with swallowing


• hives or welts


• itching


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• redness of the 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

• Acid or sour stomach


• belching


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• continuing ringing or buzzing or other unexplained noise in ears


• diarrhea


• difficulty having a bowel movement (stool)


• dizziness


• feeling of indigestion


• hair loss or thinning of the hair


• hearing loss


• hiccups


• indigestion


• lack or loss of strength


• loss of appetite


• pain in the chest below the breastbone


• stomach discomfort, upset, or pain


• swelling or inflammation of the mouth


• weight loss

Less common

• Feeling of warmth


• pain or discomfort in chest, upper stomach, or throat


• redness of the face, neck, arms, and occasionally, upper chest


• sudden sweating


• unusually warm skin

Rare

• Abdominal or stomach distension or pain


• abnormal dreams


• blemishes on the skin


• bumps on the skin


• burning, dry, or itching eyes


• change in taste


• change in walking and balance


• clumsiness or unsteadiness


• confusion about identity, place, and time


• difficulty with moving


• discharge, excessive tearing


• excess air or gas in the stomach


• extreme thirst


• false or unusual sense of well-being


• flushed, dry skin


• frequent urination


• fruit-like breath odor


• full feeling


• heartburn


• increased hunger


• increased sensitivity of the skin to sunlight


• increased urination


• increased volume of pale, dilute urine


• joint pain


• muscle aching or cramping


• muscle stiffness or weakness


• oily skin


• passing gas


• pimples


• redness or other discoloration of the skin


• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid


• severe constipation


• severe sunburn


• sleepiness


• sleeplessness


• sweating


• swollen joints


• trouble performing routine tasks


• trouble sleeping


• unable to sleep


• unexplained weight loss


• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness


• weight gain


• white patches in the mouth or throat or on the tongue


• white patches with diaper rash

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: fosaprepitant Intravenous side effects (in more detail)

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