Retrovir 250mg Capsules

1. Name Of The Medicinal Product

Retrovir 250 mg capsules, hard

2. Qualitative And Quantitative Composition

Each capsule contains 250 mg zidovudine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsules, hard

Hard gelatin capsules with opaque blue cap and opaque white body coded GSJV2.

4. Clinical Particulars

4.1 Therapeutic Indications

Retrovir oral formulations are indicated in anti-retroviral combination therapy for Human Immunodeficiency Virus (HIV) infected adults and children.

Retrovir chemoprophylaxis is indicated for use in HIV-positive pregnant women (over 14 weeks of gestation) for prevention of maternal-foetal HIV transmission and for primary prophylaxis of HIV infection in newborn infants.

4.2 Posology And Method Of Administration

Retrovir should be prescribed by physicians who are experienced in the treatment of HIV infection.

Dosage in adults and adolecents weighing at least 30 kg: The usual recommended dose of Retrovir in combination with other anti-retroviral agents is 250 or 300 mg twice daily.

Dosage in children: Retrovir 100 mg capsules and Retrovir 100 mg/10 ml oral solution are available for use in children.

Weight (kg)	In the morning	In the evening	Daily dose (mg)
8-13	one 100 mg capsule	one 100 mg capsule	200
14-21	one 100 mg capsule	two 100 mg capsules	300
22-30	two 100 mg capsules	two 100 mg capsules	400
Alternatively children weighing at least 28 kg to 30 kg (included) could take:
28-30	one 250 mg capsule	one 250 mg capsule	500

Oral solution is available for dosing children less than 8kg and for those children above 8kg unable to swallow capsules (see Oral Solution SPC)

Dosage in the prevention of maternal-foetal transmission: Pregnant women (over 14 weeks of gestation) should be given 500 mg/day orally (100 mg five times per day) until the beginning of labour. During labour and delivery Retrovir should be administered intravenously at 2 mg/kg bodyweight given over one hour followed by a continuous intravenous infusion at 1 mg/kg/h until the umbilical cord is clamped.

The newborn infants should be given 2 mg/kg bodyweight orally every 6 hours starting within 12 hours after birth and continuing until 6 weeks old (e.g. a 3 kg neonate would require a 0.6 ml dose of oral solution every 6 hours). Infants unable to receive oral dosing should be given Retrovir intravenously at 1.5 mg/kg bodyweight infused over 30 minutes every 6 hours.

In case of planned caesarean, the infusion should be started 4 hours before the operation. In the event of a false labour, the Retrovir infusion should be stopped and oral dosing restarted.

Dosage adjustments in patients with haematological adverse reactions: Substitution of zidovudine should be considered in patients whose haemoglobin level or neutrophil count fall to clinically significant levels. Other potential causes of anaemia or neutropenia should be excluded. Retrovir dose reduction or interruption should be considered in the absence of alternative treatments (see sections 4.3 and 4.4).

Dosage in the elderly: Zidovudine pharmacokinetics have not been studied in patients over 65 years of age and no specific data are available. However, since special care is advised in this age group due to age-associated changes such as the decrease in renal function and alterations in haematological parameters, appropriate monitoring of patients before and during use of Retrovir is advised.

Dosage in renal impairment: The recommended dose for patients with severe renal impairment (creatinine clearance < 10 ml/min) and patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis is 100 mg every 6 to 8 hrs (300-400 mg daily). Haematological parameters and clinical response may influence the need for subsequent dosage adjustment (see section 5.2).

Dosage in hepatic impairment: Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage reductions may be necessary but, due to the large variability in zidovudine exposures in patients with moderate to severe liver disease, precise recommendations cannot be made. If monitoring of plasma zidovudine levels is not feasible, physicians will need to monitor for signs of intolerance, such as the development of haematological adverse reactions (anaemia, leucopenia, neutropenia) and reduce the dose and/or increase the interval between doses as appropriate (see section 4.4).

4.3 Contraindications

Retrovir Oral Formulations are contra-indicated in patients known to be hypersensitive to zidovudine, or to any of the excipients.

Retrovir Oral Formulations should not be given to patients with abnormally low neutrophil counts (less than 0.75 x 10⁹/litre) or abnormally low haemoglobin levels (less than 7.5 g/decilitre or 4.65 mmol/litre).

Retrovir is contra-indicated in new born infants with hyperbilirubinaemia requiring treatment other than phototherapy, or with increased transaminase levels of over five times the upper limit of normal.

4.4 Special Warnings And Precautions For Use

Retrovir is not a cure for HIV infection or AIDS. Patients receiving Retrovir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection.

The concomitant use of rifampicin or stavudine with zidovudine should be avoided (see section 4.5).

Haematological Adverse Reactions: Anaemia (usually not observed before six weeks of Retrovir therapy but occasionally occurring earlier), neutropenia (usually not observed before four weeks' therapy but sometimes occurring earlier) and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving Retrovir; These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease (see section 4.8).

Haematological parameters should be carefully monitored. For patients with advanced symptomatic HIV disease it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. Depending on the overall condition of the patient, blood tests may be performed less often, for example every 1 to 3 months.

If the haemoglobin level falls to between 7.5 g/dl (4.65 mmol/l) and 9 g/dl (5.59 mmol/l) or the neutrophil count falls to between 0.75 x 10⁹/l and 1.0 x 10⁹/l, the daily dosage may be reduced until there is evidence of marrow recovery; alternatively, recovery may be enhanced by brief (2-4 weeks) interruption of Retrovir therapy. Marrow recovery is usually observed within 2 weeks after which time Retrovir therapy at a reduced dosage may be reinstituted. In patients with significant anaemia, dosage adjustments do not necessarily eliminate the need for transfusions (see section 4.3).

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.

Mitochondrial toxicity: 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 events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events 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 recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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 PIs and lipoatrophy and 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).

Liver disease: Zidovudine clearance in patients with mild hepatic impairment without cirrhosis [Child-Pugh scores of 5-6] is similar to that seen in healthy subjects, therefore no zidovudine dose adjustment is required. In patients with moderate to severe liver disease [Child-Pugh scores of 7-15], specific dosage recommendations cannot be made due to the large variability in zidovudine exposure observed, therefore zidovudine use in this group of patients is not recommended.

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 events. In case of concomitant antiviral therapy for hepatitis B or C, please also refer to the relevant product information for these medicinal products.

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 (see section 4.2).

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, generalized and/or focal mycobacterial infections and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Patients should be cautioned about the concomitant use of self-administered medications (see section 4.5).

Patients should be advised that Retrovir therapy has not been proven to prevent the transmission of HIV to others through sexual contact or contamination with blood.

Use in Elderly and in Patients with Renal or Hepatic Impairment: see section 4.2.

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.

Patients co-infected with hepatitis C virus: The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Limited data suggests that co-administration of zidovudine with rifampicin decreases the AUC (area under the plasma concentration curve) of zidovudine by 48% ± 34%. This may result in a partial loss or total loss of efficacy of zidovudine. The concomitant use of rifampicin with zidovudine should be avoided (see section 4.4).

Zidovudine in combination with stavudine is antagonistic in vitro. The concomitant use of stavudine with zidovudine should be avoided (see section 4.4).

Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be closely monitored for haematological toxicity.

A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.

Phenytoin blood levels have been reported to be low in some patients receiving Retrovir, while in one patient a high level was noted. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both drugs.

Atovaquone: zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy

Valproic acid, fluconazole or methadone when co-administered with zidovudine have been shown to increase the AUC with a corresponding decrease in its clearance. As only limited data are available the clinical significance of these findings is unclear but if zidovudine is used concurrently with either valproic acid, fluconazole or methadone, patients should be monitored closely for potential toxicity of zidovudine.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive drugs (eg. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant therapy with any of these drugs is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.

Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine with cotrimoxazole, aerosolised pentamidine, pyrimethamine and aciclovir at doses used in prophylaxis.

Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by at least two hours.

4.6 Pregnancy And Lactation

Pregnancy:

The use of Retrovir in pregnant women over 14 weeks of gestation, with subsequent treatment of their newborn infants, has been shown to significantly reduce the rate of maternal-foetal transmission of HIV based on viral cultures in infants.

The results from the pivotal U.S. placebo-controlled study indicated that Retrovir reduced maternal-foetal transmission by approximately 70%. In this study, pregnant women had CD4 cell counts of 200 to 1818/mm³ (median in treated group 560/mm³) and began treatment therapy between weeks 14 and 34 of gestation and had no clinical indications for Retrovir therapy; their newborn infants received Retrovir until 6-weeks old.

A decision to reduce the risk of maternal transmission of HIV should be based on the balance of potential benefits and potential risk. Pregnant women considering the use of Retrovir during pregnancy for prevention of HIV transmission to their infants should be advised that transmission may still occur in some cases despite therapy.

The efficacy of zidovudine to reduce the maternal-foetal transmission in women with previously prolonged treatment with zidovudine or other antiretroviral agents or women infected with HIV strains with reduced sensitivity to zidovudine is unknown.

It is unknown whether there are any long-term consequences of in utero and infant exposure to Retrovir.

Based on the animal carcinogenicity/mutagenicity findings a carcinogenic risk to humans cannot be excluded (see section 5.3). The relevance of these findings to both infected and uninfected infants exposed to Retrovir is unknown. However, pregnant women considering using Retrovir during pregnancy should be made aware of these findings.

A large amount of data on pregnant women (more than 3000 exposed outcomes) indicate no malformative nor feto/neonatal toxitcity. Retrovir can be used during pregnancy if clinically needed. Retrovir should only be used prior to the 14th week of gestation when the potential benefit to the mother and foetus outweigh the risks. Studies in pregnant rats and rabbits given zidovudine orally at dosage levels up to 450 and 500 mg/kg/day respectively during the major period of organogenesis have revealed no evidence of teratogenicity. There was, however, a statistically significant increase in foetal resorptions in rats given 150 to 450 mg/kg/day and in rabbits given 500 mg/kg/day.

A separate study, reported subsequently, found that rats given a dosage of 3000 mg/kg/day, which is very near the oral median lethal dose (3683 mg/kg), caused marked maternal toxicity and an increase in the incidence of foetal malformations. No evidence of teratogenicity was observed in this study at the lower dosages tested (600 mg/kg/day or less).

Fertility:

Zidovudine did not impair male or female fertility in rats given oral doses of up to 450 mg/kg/day. There are no data on the effect of Retrovir on human female fertility. In men, Retrovir has not been shown to affect sperm count, morphology or motility.

Lactation:

Health experts recommend that women infected with HIV do not breast feed their infants in order to avoid the transmission of HIV. After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. Therefore, since the drug and the virus pass into breast milk it is recommended that mothers taking Retrovir do not breast feed their infants.

4.7 Effects On Ability To Drive And Use Machines

There have been no studies to investigate the effect of Retrovir on driving performance or the ability to operate machinery. Furthermore, a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless, the clinical status of the patient and the adverse reaction profile of Retrovir should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Undesirable Effects

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³. Dosage reduction or cessation of therapy may become necessary (see section 4.4).

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B₁₂ levels were low at the start of Retrovir therapy.

The following events have been reported in patients treated with Retrovir.

The adverse events considered at least possibly related to the treatment (adverse drug reactions, ADR) are listed below by body system, organ class and absolute frequency. Frequencies are defined as Very common (greater than 10%), Common (1 - 10%), Uncommon (0.1-1%), Rare (0.01-0.1%) and Very rare (less than 0.01%).

Blood and lymphatic system disorders

Common: Anaemia, neutropenia and leucopenia

Uncommon: Pancytopenia with bone marrow hypoplasia, thrombocytopenia

Rare: Pure red cell aplasia

Very rare: Aplastic anaemia

Metabolism and nutrition disorders

Rare: Lactic acidosis in the absence of hypoxaemia, anorexia

Psychiatric disorders

Rare: Anxiety and depression

Nervous system disorders

Very common: Headache

Common: Dizziness

Rare: Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence

Cardiac disorders

Rare: Cardiomyopathy

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Rare: Cough

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting, diarrhoea and abdominal pain

Uncommon: Flatulence

Rare: Pancreatitis. Oral mucosa pigmentation, taste disturbance and dyspepsia.

Hepatobiliary disorders

Common: Raised blood levels of liver enzymes and bilirubin

Rare: Liver disorders such as severe hepatomegaly with steatosis

Skin and subcutaneous tissue disorders

Uncommon: Rash and pruritis

Rare: Urticaria, nail and skin pigmentation, and sweating

Musculoskeletal and connective tissue disorders

Common: Myalgia

Uncommon: Myopathy

Renal and urinary disorders

Rare: Urinary frequency

Reproductive system and breast disorders

Rare: Gynaecomastia

General disorders and administration site disorders

Common: Malaise

Uncommon: Asthenia, fever, and generalised pain

Rare: Chest pain and influenza-like syndrome, chills

The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse reactions consistently decreases over time during the first few weeks of therapy with Retrovir.

Adverse reactions with Retrovir for the prevention of maternal-foetal transmission:

In a placebo-controlled trial, overall clinical adverse reactions and laboratory test abnormalities were similar for women in the Retrovir and placebo groups. However, there was a trend for mild and moderate anaemia to be seen more commonly prior to delivery in the zidovudine treated women.

In the same trial, haemoglobin concentrations in infants exposed to Retrovir for this indication were marginally lower than in infants in the placebo group, but transfusion was not required. Anaemia resolved within 6 weeks after completion of Retrovir therapy. Other clinical adverse reactions and laboratory test abnormalities were similar in the Retrovir and placebo groups. It is unknown whether there are any long-term consequences of in utero and infant exposure to Retrovir.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

4.9 Overdose

Symptoms and signs:

No specific symptoms or signs have been identified following acute overdose with zidovudine apart from those listed as undesirable effects such as fatigue, headache, vomiting, and occasional reports of haematological disturbances. Following a report where a patient took an unspecified quantity of zidovudine with serum levels consistent with an overdose of greater than 17 g there were no short term clinical, biochemical or haematological sequelae identified.

Treatment:

Patients should be observed closely for evidence of toxicity (see section 4.8) and given the necessary supportive therapy.

Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine but enhance the elimination of the glucuronide metabolite.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: nucleoside analogue , ATC code: J05A F01

Mode of action:

Zidovudine is an antiviral agent which is highly active in vitro against retroviruses including the Human Immunodeficiency Virus (HIV).

Zidovudine is phosphorylated in both infected and uninfected cells to the monophosphate (MP) derivative by cellular thymidine kinase. Subsequent phosphorylation of zidovudine-MP to the diphosphate (DP), and then the triphosphate (TP) derivative is catalysed by cellular thymidylate kinase and non-specific kinases respectively. Zidovudine-TP acts as an inhibitor of and substrate for the viral reverse transcriptase. The formation of further proviral DNA is blocked by incorporation of zidovudine-MP into the chain and subsequent chain termination. Competition by zidovudine-TP for HIV reverse transcriptase is approximately 100-fold greater than for cellular DNA polymerase alpha.

Clinical virology:

The relationships between in vitro susceptibility of HIV to zidovudine and clinical response to therapy remain under investigation. In vitro sensitivity testing has not been standardised and results may therefore vary according to methodological factors. Reduced in vitro sensitivity to zidovudine has been reported for HIV isolates from patients who have received prolonged courses of Retrovir therapy. The available information indicates that for early HIV disease, the frequency and degree of reduction of in vitro sensitivity is notably less than for advanced disease.

The reduction of sensitivity with the emergence of zidovudine resistant strains limits the usefulness of zidovudine monotherapy clinically. In clinical studies, clinical end-point data indicate that zidovudine, particularly in combination with lamivudine, and also with didanosine or zalcitabine results in a significant reduction in the risk of disease progression and mortality. The use of a protease inhibitor in a combination of zidovudine and lamivudine, has been shown to confer additional benefit in delaying disease progression, and improving survival compared to the double combination on its own.

The anti-viral effectiveness in vitro of combinations of anti-retroviral agents are being investigated. Clinical and in vitro studies of zidovudine in combination with lamivudine indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. Furthermore there is clinical evidence that zidovudine plus lamivudine delays the emergence of zidovudine resistance in anti-retroviral naive patients.

In some in vitro studies zidovudine has been shown to act additively or synergistically with a number of anti-HIV agents, such as lamivudine, didanosine, and interferon-alpha, inhibiting the replication of HIV in cell culture. However, in vitro studies with triple combinations of nucleoside analogues or two nucleoside analogues and a protease inhibitor have been shown to be more effective in inhibiting HIV-1 induced cytopathic effects than one or two drug combinations.

Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other nucleosides, allowing for the subsequent use of any of the other approved reverse transcriptase inhibitors.

Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the other approved nucleoside reverse transcriptase inhibitors. Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options.

In the US ACTGO76 trial, Retrovir was shown to be effective in reducing the rate of maternal-foetal transmission of HIV-1 (23% infection rate for placebo versus 8% for zidovudine) when administered (100 mg five times a day) to HIV-positive pregnant women (from week 14-34 of pregnancy) and their newborn infants (2 mg/kg every 6 hours) until 6 weeks of age. In the shorter duration 1998 Thailand CDC study, use of oral Retrovir therapy only (300 mg twice daily), from week 36 of pregnancy until delivery, also reduced the rate of maternal-foetal transmission of HIV (19% infection rate for placebo versus 9% for zidovudine). These data, and data from a published study comparing zidovudine regimens to prevent maternal-foetal HIV transmission have shown that short maternal treatments (from week 36 of pregnancy) are less efficacious than longer maternal treatments (from week 14-34 of pregnancy) in the reduction of perinatal HIV transmission.

5.2 Pharmacokinetic Properties

Adults:

Absorption:

Zidovudine is well absorbed from the gut and, at all dose levels studied, the bioavailability was 60-70%. From a bioequivalence study, steady-state mean (CV%) C[ss]max, C[ss]min, and AUC[ss] values in 16 patients receiving zidovudine 300 mg tablets twice daily were 8.57 (54%) microM (2.29 μg/ml), 0.08 (96%) microM (0.02 μg/ml), and 8.39 (40%) h*microM (2.24 h*μg/ml), respectively.

Distribution:

From studies with intravenous Retrovir, the mean terminal plasma half-life was 1.1 hours, the mean total body clearance was 27.1 ml/min/kg and the apparent volume of distribution was 1.6 Litres/kg.

In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio 2 to 4 hours after dosing was found to be approximately 0.5. Data indicate that zidovudine crosses the placenta and is found in amniotic fluid and foetal blood. Zidovudine has also been detected in semen and milk.

Plasma protein binding is relatively low (34 to 38%) and drug interactions involving binding site displacement are not anticipated.

Metabolism:

Zidovudine is primarily eliminated by hepatic conjugation to an inactive glucoronidated metabolite. The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50-80% of the administered dose eliminated by renal excretion. 3'-amino-3'-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous dosing.

Excretion:

Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that significant tubular secretion takes place.

Paediatrics:

Absorption:

In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and, at all dose levels studied, its bioavailability was 60-74% with a mean of 65%. C^ssmax levels were 4.45µM (1.19 µg/ml) following a dose of 120 mg Retrovir (in solution)/m² body surface area and 7.7 µM (2.06 µg/ml) at 180 mg/m² body surface area. Dosages of 180 mg/m² four times daily in children produced similar systemic exposure (24 hour AUC 40.0 hr µM or 10.7 hr µg/ml) as doses of 200 mg six times daily in adults (40.7 hr µM or 10.9 hr µg/ml).

Distribution:

With intravenous dosing, the mean terminal plasma half-life and total body clearance were 1.5 hours and 30.9 ml/min/kg respectively.

In children the mean cerebrospinal fluid/plasma zidovudine concentration ratio ranged from 0.52-0.85, as determined during oral therapy 0.5 to 4 hours after dosing and was 0.87 as determined during intravenous therapy 1-5 hours after a 1 hour infusion. During continuous intravenous infusion, the mean steady-state cerebrospinal fluid/plasma concentration ratio was 0.24.

Metabolism:

The major metabolite is 5'-glucuronide. After intravenous dosing, 29% of the dose was recovered unchanged in the urine and 45% excreted as the glucuronide.

Excretion:

Renal clearance of zidovudine greatly exceeds creatinine clearance indicating that significant tubular secretion takes place.

The data available on the pharmacokinetics in neonates and young infants indicate that glucuronidation of zidovudine is reduced with a consequent increase in bioavailability, reduction in clearance and longer half-life in infants less than 14 days old but thereafter the pharmacokinetics appear similar to those reported in adults.

Pregnancy:

The pharmacokinetics of zidovudine has been investigated in a study of eight women during the third trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in infant plasma at birth were essentially equal to those in maternal plasma at delivery.

Elderly:

No specific data are available on the pharmacokinetics of zidovudine in the elderly.

Renal impairment:

In patients with severe renal impairment, apparent zidovudine clearance after oral zidovudine administration was approximately 50% of that reported in healthy subjects with normal renal function. Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of the inactive glucuronide metabolite is increased (see section 4.2).

Hepatic impairment:

There are limited data on the pharmacokinetics of zidovudine in patients with hepatic impairment (see section 4.2).

5.3 Preclinical Safety Data

Mutagenicity:

No evidence of mutagenicity was observed in the Ames test. However, zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects were observed in an in vitro study in human lymphocytes and in in vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. A study of the peripheral blood lymphocytes of eleven AIDS patients showed a higher chromosome breakage frequency in those who had received Retrovir than in those who had not. A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers. A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero to the combination sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.

Carcinogenicity:

In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelial tumours were observed. A subsequent intravaginal carcinogenicity study confirmed the hypothesis that the vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium to high concentrations of unmetabolised zidovudine in urine. There were no other drug-related tumours observed in either sex of either species.

In addition, two transplacental carcinogenicity studies have been conducted in mice. One study, by the US National Cancer Institute, administered zidovudine at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in the incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the highest dose level (420 mg/kg term body weight).

In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine acts as a transplacental carcinogen.

It is concluded that the transplacental carcinogenicity data from the first study represents a hypothetical risk, whereas the reduction in risk of maternal transfection of HIV to the uninfected child by the use of zidovudine in pregnancy has been well proven.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule core:

Maize starch

Microcrystalline Cellulose

Sodium Starch Glycollate

Magnesium Stearate.

Capsule coating:

E171 Titanium dioxide

Gelatin

Indigo carmine E132

Printing ink:

Opacode S-1-27794 Black (contains Black Iron Oxide E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original package.

6.5 Nature And Contents Of Container

PVC/aluminium foil blister pack containing 40 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

8. Marketing Authorisation Number(S)

PL 35728/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 03 March 1987

Date of last renewal:14 July 2011

10. Date Of Revision Of The Text

06 January 2012

Isosorbide Mononitrate Extended Release

Unknown Title

DESCRIPTION

Isosorbide Mononitrate (ISMN), an organic nitrate and the major biologically active metabolite of isosorbide dinitrate (ISDN), is a vasodilator with effects on both arteries and veins.

Each Isosorbide mononitrate extended-release tablet, for oral administration contains 60 mg of ISMN. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, compressible sugar, hydroxypropyl methylcellulose, yellow iron oxide, lactose monohydrate, magnesium stearate.

The molecular formula of ISMN is C6H9NO6 and the molecular weight is 191.14.

The chemical name for ISMN is 1,4:3,6-dianhydro-D-glucitol 5-nitrate; the compound has the following structural formula:

ISMN is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of about 90°C, and an optical rotation of +144° (2% in water, 20°C).

ISMN is freely soluble in water, ethanol, methanol, chloroform, ethyl acetate and dichloromethane.

CLINICAL PHARMACOLOGY

Mechanism of Action

This product is an oral extended-release formulation of ISMN, the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate.

The principal pharmacological action of ISMN and all organic nitrates in general is relaxation of vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood, decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction and coronary dilatation remains undefined.

Pharmacodynamics

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored.

Isosorbide mononitrate extended-release tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but their effects (although better than placebo) are less than or at best equal to the effects of the first dose of 60 mg.

Pharmacokinetics and Metabolism

After oral administration of ISMN as a solution or immediate-release tablets, maximum plasma concentrations of ISMN are achieved in 30 to 60 minutes, with an absolute bioavailability of approximately 100%. After intravenous administration, ISMN is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6 to 0.7 L/kg. ISMN is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. ISMN is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. ISMN is cleared by denitration to isosorbide and glucuronidation as the mononitrate, with 96% of the administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. At least six different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least five metabolites. The metabolites are not pharmacologically active.  Renal clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of ISMN is approximately 5 hours.

The disposition of ISMN in patients with various degrees of renal insufficiency, liver cirrhosis, or cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The elimination half-life of ISMN was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing.

The pharmacokinetics and/or bioavailability of Isosorbide mononitrate extended-release tablets have been studied in both normal volunteers and patients following single-and multiple-dose administration. Data from these studies suggest that the pharmacokinetics of ISMN administered as Isosorbide mononitrate extended-release tablets are similar between normal healthy volunteers and patients with angina pectoris. In single and multiple-dose studies, the pharmacokinetics of ISMN were dose proportional between 30 mg and 240 mg.

In a multiple-dose study, the effect of age on the pharmacokinetic profile of Isosorbide Mononitrate Extended Release 60 mg and 120 mg (2 x 60 mg) tablets was evaluated in subjects ≥ 45 years. The results of that study indicate that there are no significant differences in any of the pharmacokinetic variables of ISMN between elderly (≥ 65 years) and younger individuals (45 to 64 years) for the ISMN extended-release 60 mg dose. The administration of Isosorbide mononitrate extended-release tablets 120 mg (2 x 60 mg) tablets every 24 hours for 7 days) produced a dose-proportional increase in Cmax and AUC, without changes in Tmax or the terminal half-life. The older group (65 to 74 years) showed 30% lower apparent oral clearance (CI/F) following the higher dose, i.e., 120 mg, compared to the younger group (45 to 64 years); CI/F was not different between the two groups following the 60 mg regimen. While CI/F was independent of dose in the younger group, the older group showed slightly lower CI/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the two age groups, however, were not statistically significant. In the same study, females showed a slight (15%) reduction in clearance when the dose was increased. Females showed higher AUCs and Cmax compared to males, but these differences were accounted for by differences in body weight between the two groups. When the data were analyzed using age as a variable, the results indicated that there were no significant differences in any of the pharmacokinetic variables of ISMN between older (≥65 years) and younger individuals (45 to 64 years). The results of this study, however, should be viewed with caution due to the small numbers of subjects in each age subgroup and consequently the lack of sufficient statistical power.

The following table summarizes key pharmacokinetic parameters of Isosorbide Mononitrate (ISMN) after single- and multiple-dose administration of ISMN as an oral solution or Isosorbide mononitrate extended-release tablets:

	SINGLE-DOSE STUDIES		MULTIPLE-DOSE STUDIES
PARAMETER	ISMN 60 mg	ISMNextended-release tablets60 mg	ISMNextended-releasetablets60 mg	ISMNextended-release tablets120 mg
Cmax (ng/mL)	1242 to 1534	424 to 541	557 to 572	1151 to 1180
Tmax (hr)	0.6 to 0.7	3.1 to 4.5	2.9 to 4.2	3.1 to 3.2
AUC (ng·hr/mL)	8189 to 8313	5990 to 7452	6625 to 7555	14241 to 16800
t ½ (hr)	4.8 to 5.1	6.3 to 6.6	6.2 to 6.3	6.2 to 6.4
CI/F (mL/min)	120 to 122	151 to 187	132 to 151	119 to 140

Food Effects

The influence of food on the bioavailability of ISMN after single-dose administration of Isosorbide mononitrate extended-release tablets 60 mg was evaluated in three different studies involving either a “light” breakfast or a high-calorie, high-fat breakfast. Results of these studies indicate that concomitant food intake may decrease the rate (increase in Tmax) but not the extent (AUC) of absorption of ISMN.

Clinical Trials

Controlled trials with Isosorbide mononitrate extended-release tablets have demonstrated antianginal activity following acute and chronic dosing. Administration of Isosorbide mononitrate extended-release tablets once daily, taken early in the morning on arising, provided at least 12 hours of antianginal activity.

In a placebo-control parallel study, 30 mg, 60 mg, 120 mg, and 240 mg of Isosorbide mononitrate extended-release tablets were administered once daily for up to 6 weeks. Prior to randomization, all patients completed a 1-to 3-week single-blind placebo phase to demonstrate nitrate responsiveness and total exercise treadmill time reproducibility. Exercise tolerance tests using the Bruce Protocol were conducted prior to and at 4 and 12 hours after the morning dose on days 1, 7, 14, 28 and 42 of the double-blind period. Isosorbide mononitrate extended-release tablets 30 mg and 60 mg (only doses

evaluated acutely) demonstrated a significant increase from baseline in total treadmill time relative to placebo at 4 and 12 hours after the administration of the first dose. At day 42, the 120 mg and 240 mg dose of Isosorbide mononitrate extended-release tablets demonstrated a significant increase in total treadmill time at 4 and 12 hours post dosing, but by day 42 the 30 mg and 60 mg doses no longer were differentiable from placebo. Throughout chronic dosing rebound was not observed in any Isosorbide mononitrate extended-release tablets treatment group.

Pooled data from two other trials, comparing Isosorbide mononitrate extended-release tablets 60 mg once daily, isosorbide dinitrate 30 mg QID, and placebo QID in patients with chronic stable angina using a randomized, double-blind, three-way crossover design found statistically significant increases in exercise tolerance times for Isosorbide mononitrate extended-release tablets compared to placebo at hours 4, 8 and 12 and to isosorbide dinitrate at hour 4. The increases in exercise tolerance on day 14, although statistically significant compared to placebo, were about half of that seen on day 1 of the trial.

INDICATIONS AND USAGE

Isosorbide mononitrate extended-release tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of oral ISMN is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

CONTRAINDICATIONS

Isosorbide mononitrate extended-release tablets are contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

WARNINGS Amplification of the vasodilatory effects of Isosorbide mononitrate extended-release tablets by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of ISMN in patients with acute myocardial infarction or congestive heart failure have not been established; because the effects of ISMN are difficult to terminate rapidly, this drug is not recommended in these settings.

If ISMN is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

PRECAUTIONS

General

Severe hypotension, particularly with upright posture, may occur with even small doses of ISMN. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by ISMN may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

In industrial workers who have had long term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occured during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. The importance of these observations to the routine, clinical use of oral ISMN is not known.

Information for Patients

Patients should be told that the antianginal efficacy of Isosorbide mononitrate extended-release tablets can be maintained by carefully following the prescribed schedule of dosing. For most patients, this can be accomplished by taking the dose on arising.

As with other nitrates, daily headaches sometimes accompany treatment with ISMN. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with ISMN, since loss of headache may be associated with simultaneous loss of antianginal efficacy. Aspirin or acetaminophen often successfully relieves ISMN induced headaches with no deleterious effect on ISMN’s antianginal efficacy.

Treatment with ISMN may be associated with light-headedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

Drug Interactions

The vasodilating effects of ISMN may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination.

Dose adjustments of either class of agents may be necessary.

DRUG & OR LABORATORY TEST INTERACTIONS

Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing falsely low readings in serum cholesterol determinations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed in rats exposed to Isosorbide Mononitrate (ISMN) in their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining duration of a study in which males were dosed for up to 121 weeks and females were dosed for up to 137 weeks. No evidence of carcinogenicity was observed in mice exposed to isosorbide mononitrate in their diets for up to 104 weeks at doses of up to 900 mg/kg/day.

ISMN did not produce gene mutations (Ames test, mouse lymphoma test) or chromosome aberrations (human lymphocyte and mouse micronucleus tests) at biologically relevant concentrations.

No effects on fertility were observed in a study in which male and female rats were administered doses of up to 750 mg/kg/day beginning, in males, 9 weeks prior to mating, and in females, 2 weeks prior to mating.

Pregnancy

Teratogenic Effects

Pregnancy Category B. In studies designed to detect effects of ISMN on embryo-fetal development, doses of up to 240 or 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects. These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg woman) when comparison is based on body weight; when comparison is based on body surface area, the rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Isosorbide mononitrate extended-release tablets should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant rats were administered oral doses of 750 (but not 300) mg ISMN/kg/day during late gestation and lactation. This dose (about 312 times the human dose when comparison is based on body weight and 54 times the human dose when comparison is based on body surface area) was associated with decreases in maternal weight gain and motor activity and evidence of impaired lactation.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of ISMN in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isosorbide Mononitrate Extended-release Tablets did not include sufficient information on patients age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience for Isosorbide Mononitrate Extended Release Tablets has not identified differences in response between elderly and younger patients. Clinical experience for organic nitrates reported in the literature identified a potential for severe hypotension and increased sensitivity to nitrates in the elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients may have reduced baroreceptor function and may develop severe orthostatic hypotension when vasodilators are used. Isosorbide Mononitrate Extended-release Tablets should therefore be used with caution in elderly patients who may be volume depleted, on multiple medications or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Elderly patients may be more susceptible to hypotension and may be at greater risk of falling at therapeutic doses of nitroglycerin.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.

ADVERSE REACTIONS

The table below shows the frequencies of the adverse events that occurred in >5% of the subjects in three placebo-controlled North American studies, in which patients in the active treatment arm received 30 mg, 60 mg, 120 mg or 240 mg of ISMN as Isosorbide mononitrate extended-release tablets once daily. In parentheses, the same table shows the frequencies with which these adverse events were associated with the discontinuation of treatment. Overall, 8% of the patients who received 30 mg, 60 mg, 120 mg or 240 mg of ISMN in the three placebo-controlled North American

studies discontinued treatment because of adverse events. Most of these discontinued because of headache. Dizziness was rarely associated with withdrawal from these studies. Since headache appears to be a dose-related adverse effect and tends to disappear with continued treatment, it is recommended that Isosorbide mononitrate extended-release tablets treatment be initiated at low doses for several days

before being increased to desired levels.

FREQUENCY AND ADVERSE EVENTS (DISCONTINUED)*

Three Controlled North American Studies
Dose	Placebo	30 mg	60 mg	120 mg**	240 mg**
* Some individuals discontinued for multiple reasons
** Patients were started on 60 mg and titrated to their final dose.
Patients	96	60	102	65	65
Headache	15% (0%)	38% (5%)	51% (8%)	42% (5%)	57% (8%)
Dizziness	4% (0%)	8% (0%)	11% (1%)	9% (2%)	9% (2%)

In addition, the three North American trials were pooled with 11 controlled trials conducted in Europe. Among the 14 controlled trials, a total of 711 patients were randomized to Isosorbide mononitrate extended-release tablets. When the pooled data were reviewed, headache and dizziness were the

only adverse events that were reported by >5% of patients. Other adverse events, each reported by ≤5% of exposed patients, and in many cases of uncertain relation to drug treatment, were:

Autonomic Nervous System Disorders: Dry mouth, hot flushes.

Body as a Whole: Asthenia, back pain, chest pain, edema, fatigue, fever, flu-like symptoms, malaise, rigors.

Cardiovascular Disorders, General: Cardiac failure, hypertension, hypotension.

Central and Peripheral Nervous System Disorders: Dizziness, headache, hypoesthesia, migraine, neuritis, paresis, paresthesia, ptosis, tremor, vertigo.

Gastrointestinal System Disorders: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gastric ulcer, gastritis, glossitis, hemorrhagic gastric ulcer, hemorrhoids, loose stools, melena, nausea, vomiting.

Hearing and Vestibular Disorders: Earache, tinnitus, tympanic membrane perforation.

Heart Rate and Rhythm Disorders: Arrhythmia, arrhythmia atrial, atrial fibrillation, bradycardia, bundle branch block, extrasystole, palpitation, tachycardia, ventricular tachycardia.

Liver and Biliary System Disorders: SGOT increase, SGPT increase.

Metabolic and Nutritional Disorders: Hyperuricemia, hypokalemia.

Musculoskeletal System Disorders: Arthralgia, frozen shoulder, muscle weakness, musculoskeletal pain, myalgia, myositis,tendon disorder, torticollis.

Myo-, Endo-, Pericardial and Valve Disorders: Angina pectoris aggravated, heart murmur, heart sound abnormal, myocardial infarction, Q-Wave abnormality.

Platelet, Bleeding and Clotting Disorders: Purpura, thrombocytopenia.

Psychiatric Disorders: Anxiety, concentration impaired, confusion, decreased libido, depression, impotence, insomnia, nervousness, paroniria, somnolence.

Red Blood Cell Disorder: Hypochromic anemia.

Reproductive Disorders, Female: Atrophic vaginitis, breast pain.

Resistance Mechanism Disorders: Bacterial infection,moniliasis, viral infection.

Respiratory System Disorders: Bronchitis, bronchospasm, coughing, dyspnea, increased sputum, nasal congestion, pharyngitis, pneumonia, pulmonary infiltration, rales, rhinitis, sinusitis.

Skin and Appendages Disorders: Acne, hair texture abnormal, increased sweating, pruritus, rash, skin nodule.

Urinary System Disorders: Polyuria, renal calculus, urinary tract infection.

Vascular (Extracardiac) Disorders: Flushing, intermittent claudication, leg ulcer, varicose vein.

Vision Disorders: Conjunctivitis, photophobia, vision abnormal.

In addition, the following spontaneous adverse event has been reported during the marketing of Isosorbide Mononitrate (ISMN): syncope.

OVERDOSAGE

Hemodynamic Effects 

The ill effects of ISMN overdose are generally the results of ISMN’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial

pressure, with any or all of persistent throbbing headache, confusion and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced

ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis;coma; seizures and death.

Laboratory determinations of serum levels of ISMN and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ISMN overdose.

There are no data suggesting what dose of ISMN is likely to be life threatening in humans. In rats and mice, there is significant lethality at doses of 2000 mg/kg and 3000 mg/kg, respectively.

No data are available to suggest physiological maneuvers (e.g. maneuvers to change the pH of the urine) that might accelerate elimination of ISMN. In particular, dialysis is known to be ineffective in removing ISMN from the body.

No specific antagonist to the vasodilator effects of ISMN is known, and no intervention has been subject to controlled study as a therapy of ISMN overdose. Because the hypotension associated with ISMN overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward an increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of ISMN overdose in these patients may be

subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Methemoglobinemia has been reported in patients receiving other organic nitrates, and it probably could also occur as a side effect of ISMN. Certainly nitrate ions liberated during metabolism of ISMN can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moiety of ISMN is quantitatively applied to oxidation of hemoglobin, about 2 mg/kg of ISMN should be required before any of these patients manifest clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of ISMN. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 7.8 - 11.1 mg of ISMN per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients 0who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

DOSAGE AND ADMINISTRATION

The recommended starting dose of Isosorbide mononitrate extended-release tablets is 30 mg (given as 1/2 of a 60 mg tablet) or 60 mg (given as a single tablet) once daily. After several days the dosage may be increased to 120 mg (given as two 60 mg tablets) once daily. Rarely, 240 mg may be required. The daily dose of Isosorbide mononitrate extended-release tablets should be taken in the morning on arising. Isosorbide mononitrate extended-release tablets should not be chewed or crushed and should be swallowed together with a half-glassful of fluid.

HOW SUPPLIED

Isosorbide mononitrate extended-release tablets (60 mg): Light yellow, biconvex oval shaped

tablets,scored on both sides and embossed ‘DX 31’ on one side.

Bottle of 90    NDC 47781-275-09

Bottle of 500  NDC 47781-275-05

Storage and Handling

Store at 20° to 25°C (68° to 77°F) (see USP Controlled Room Temperature). Protect from excessive moisture.

Manufactured by:

Dexcel Ltd.

1 Dexcel St.

Or-Akiva 30600

Israel

Distributed by:

Alvogen, Inc.

Pine Brook, NJ 07058

ISS 12/11

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

ISOSORBIDE MONONITRATE  EXTENDED RELEASE isosorbide mononitrate  tablet, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 47781-275 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ISOSORBIDE MONONITRATE (ISOSORBIDE) ISOSORBIDE MONONITRATE 60 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   SUCROSE   HYDROXYPROPYL CELLULOSE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color YELLOW (light) Score 2 pieces Shape OVAL (biconvex) Size 13mm Flavor Imprint Code DX;31 Contains

Packaging # NDC Package Description Multilevel Packaging 1 47781-275-09 90 TABLET In 1 BOTTLE None 2 47781-275-05 500 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075522	06/07/2010

Labeler - Alvogen, Inc. (008057330)

Registrant - Dexcel, Ltd. (600534200)

Establishment
Name	Address	ID/FEI	Operations
Dexcel, Ltd.		600534200	MANUFACTURE

Revised: 12/2011Alvogen, Inc.

Ferragen

Generic Name: multivitamin with iron (MUL tee VYE ta mins with i ron)

Brand Names:

What is Ferragen (multivitamin with iron)?

Multivitamin are a combination of many different vitamins that are normally found in foods and other natural sources.

Iron is normally found in foods like red meat. In the body, iron becomes a part of your hemoglobin (HEEM o glo bin) and myoglobin (MY o glo bin). Hemoglobin carries oxygen through your blood to tissues and organs. Myoglobin helps your muscle cells store oxygen.

Multivitamin and iron are used to provide vitamins and iron that are not taken in through the diet. They are also used to treat iron or vitamin deficiencies caused by illness, pregnancy, poor nutrition, digestive disorders, and many other conditions.

Multivitamin and iron may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Ferragen (multivitamin with iron)?

Never take more than the recommended dose of a multivitamin. Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects. Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects. Iron and other minerals contained in a multivitamin can also cause serious overdose symptoms if you take too much.

Overdose symptoms may include severe stomach pain, vomiting, bloody diarrhea, coughing up blood, constipation, loss of appetite, hair loss, peeling skin, warmth or tingly feeling, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine or stools, black and tarry stools, pale skin, easy bruising or bleeding, weakness, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin with iron.

What should I discuss with my healthcare provider before taking Ferragen (multivitamin with iron)?

Iron and certain vitamins can cause serious or life-threatening side effects if taken in large doses. Do not take more of this medication than directed on the label or prescribed by your doctor.

If you have any medical conditions, ask your doctor before taking a multivitamin with iron. If you have certain conditions, you may need a certain vitamin formulation or special tests while taking this product.

Do not take multivitamin with iron without telling your doctor if you are pregnant or plan to become pregnant. Some vitamins and minerals can harm an unborn baby if taken in large doses. You may need to use a prenatal vitamin specially formulated for pregnant women. Multivitamin can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Ferragen (multivitamin with iron)?

Use this medication as directed on the label, or as your doctor has prescribed. Do not use the medication in larger amounts or for longer than recommended.

Never take more than the recommended dose of multivitamin with iron. Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Many multivitamin products also contain minerals such as calcium, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Take your multivitamin with a full glass of water. You may take the multivitamin with food if it upsets your stomach.

The chewable tablet must be chewed or allowed to dissolve in the mouth before swallowing.

Measure the liquid form of this multivitamin using a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Liquid multivitamin may sometimes be mixed with water, fruit juice, or infant formula (but not milk or other dairy products). Follow the directions on the medicine label.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow the pill whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

It is important to take multivitamin with iron regularly to get the most benefit.

Store this medication at room temperature away from moisture and heat. Keep the liquid medicine from freezing.

Store multivitamin in their original container. Storing multivitamin in a glass container can ruin the medication.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects. Iron and other minerals contained in a multivitamin can also cause serious overdose symptoms.

Overdose symptoms may include severe stomach pain, vomiting, bloody diarrhea, coughing up blood, constipation, loss of appetite, hair loss, peeling skin, warmth or tingly feeling, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine or stools, black and tarry stools, pale skin, easy bruising or bleeding, weakness, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

What should I avoid while taking Ferragen (multivitamin with iron)?

Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Avoid the regular use of salt substitutes in your diet if your multivitamin contains potassium. If you are on a low-salt diet, ask your doctor before taking a vitamin or mineral supplement.

Avoid taking an antibiotic medicine within 2 hours before or after you take multivitamin with iron. This is especially important if you are taking an antibiotic such as ciprofloxacin (Cipro), demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), norfloxacin (Noroxin), ofloxacin (Floxin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

Certain foods can also make it harder for your body to absorb iron. Avoid taking this multivitamin within 1 hour before or 2 hours after eating fish, meat, liver, and whole grain or "fortified" breads or cereals.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin.

Ferragen (multivitamin with iron) 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 if you have serious side effects such as:

• 
  

  bright red blood in your stools; or

  
  


• 
  

  pain in your chest or throat when swallowing a ferrous fumarate tablet.

  
  

When taken as directed, multivitamin are not expected to cause serious side effects. Less serious side effects may include:

• 
  

  constipation, diarrhea;

  
  


• 
  

  nausea, vomiting, heartburn;

  
  


• 
  

  stomach pain, upset stomach;

  
  


• 
  

  black or dark-colored stools or urine;

  
  


• 
  

  temporary staining of the teeth;

  
  


• 
  

  headache; or

  
  


• 
  

  unusual or unpleasant taste in your mouth.

  
  

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

What other drugs will affect Ferragen (multivitamin with iron)?

Vitamin and mineral supplements can interact with certain medications, or affect how medications work in your body. Before taking multivitamin with iron, tell your doctor if you also use:

• 
  

  acetohydroxamic acid (Lithostat);

  
  


• 
  

  cimetidine (Tagamet);

  
  


• 
  

  deferoxamine (Desferal);

  
  


• 
  

  etidronate (Didronel);

  
  


• 
  

  diuretics (water pills);

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  tretinoin (Vesanoid);

  
  


• 
  

  isotretinoin (Accutane, Amnesteen, Clavaris, Sotret);

  
  


• 
  

  dimercaprol (an injection used to treat poisoning by arsenic, lead, or mercury);

  
  


• 
  

  penicillamine (Cuprimine);

  
  


• 
  

  pancrelipase (Cotazym, Creon, Ilozyme, Pancrease, Ultrase);

  
  


• 
  

  trimethoprim and sulfamethoxazole (Cotrim, Bactrim, Septra, TMP/SMX); or

  
  


• 
  

  an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Cataflam, Voltaren), etodolac (Lodine), indomethacin (Indocin), ketoprofen (Orudis), and others.

  
  

This list is not complete and there may be other medications that can interact with or be affected by multivitamin with iron. 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 Ferragen resources

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

• Multivitamin with Iron Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Anemagen MedFacts Consumer Leaflet (Wolters Kluwer)


• BiferaRx MedFacts Consumer Leaflet (Wolters Kluwer)


• Chromagen Forte MedFacts Consumer Leaflet (Wolters Kluwer)


• Ferocon MedFacts Consumer Leaflet (Wolters Kluwer)


• Ferotrin Prescribing Information (FDA)


• Ferralet 90 Prescribing Information (FDA)


• Ferralet 90 MedFacts Consumer Leaflet (Wolters Kluwer)


• Ferrex 150 Forte Prescribing Information (FDA)


• Ferrex 150 Forte Plus Prescribing Information (FDA)


• Ferrex 150 Forte Plus MedFacts Consumer Leaflet (Wolters Kluwer)


• Ferrex 28 Prescribing Information (FDA)


• FerroGels Forte MedFacts Consumer Leaflet (Wolters Kluwer)


• FerroGels Forte Prescribing Information (FDA)


• FoliTab 500 MedFacts Consumer Leaflet (Wolters Kluwer)


• Fumatinic MedFacts Consumer Leaflet (Wolters Kluwer)


• Hematogen Forte Prescribing Information (FDA)


• Integra MedFacts Consumer Leaflet (Wolters Kluwer)


• Integra F MedFacts Consumer Leaflet (Wolters Kluwer)


• Integra F Prescribing Information (FDA)


• Integra Plus MedFacts Consumer Leaflet (Wolters Kluwer)


• Integra Plus Prescribing Information (FDA)


• Irospan 24/6 MedFacts Consumer Leaflet (Wolters Kluwer)


• Irospan 24/6 Prescribing Information (FDA)


• NovaFerrum Prescribing Information (FDA)


• NovaFerrum MedFacts Consumer Leaflet (Wolters Kluwer)


• Proferrin-Forte MedFacts Consumer Leaflet (Wolters Kluwer)


• Tricon Prescribing Information (FDA)

Compare Ferragen with other medications

• Anemia
• Vitamin/Mineral Supplementation and Deficiency

Where can I get more information?

• Your pharmacist can provide more information about multivitamin with iron.

See also: Ferragen side effects (in more detail)

hydroxychloroquine

Generic Name: hydroxychloroquine (hye drox ee KLOR oh kwin)

Brand names: Plaquenil Sulfate, Quineprox

What is hydroxychloroquine?

Hydroxychloroquine is used to treat or prevent malaria, a disease caused by parasites. Parasites that cause malaria typically enter the body through the bite of a mosquito. Malaria is common in areas such as Africa, South America, and Southern Asia.

Hydroxychloroquine is also used to treat symptoms of rheumatoid arthritis and discoid or systemic lupus erythematosus.

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

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

You should not use this medication if you are allergic to hydroxychloroquine, or if you have a history of vision changes or damage to your retina caused by hydroxychloroquine or similar anti-malaria medications.

Before using hydroxychloroquine, tell your doctor if you are allergic to any drugs, or if you have psoriasis, porphyria, liver disease, alcoholism, or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Call a poison control center at once and then seek emergency medical attention if you think you have used too much of this medicine. An overdose of hydroxychloroquine can be fatal, especially in children. Take this medicine for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Contact your doctor as soon as possible if you have been exposed to malaria, or if you have fever or other symptoms of illness during or after a stay in an area where malaria is common.

When treating lupus or arthritis, tell your doctor if your symptoms do not improve after 6 months of treatment.

If you take hydroxychloroquine long-term, your doctor may need to check your knee and ankle reflexes and also do blood tests on a regular basis to check for harmful side effects. Your vision may also need to be tested every 3 months. Do not miss any scheduled appointments.

Hydroxychloroquine should not be used for long-term treatment in children.

What should I discuss with my health care provider before taking hydroxychloroquine?

You should not use this medication if you are allergic to hydroxychloroquine, or if you have a history of vision changes or damage to your retina caused by hydroxychloroquine or similar anti-malaria medications.

Hydroxychloroquine should not be used for long-term treatment in children.

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

• 
  

  psoriasis;

  
  


• 
  

  porphyria;

  
  


• 
  

  liver disease;

  
  


• 
  

  alcoholism; or

  
  


• 
  

  glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

  
  

It is not known whether hydroxychloroquine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Malaria is more likely to cause death in a pregnant woman. If you are pregnant, talk with your doctor about the risks of traveling to areas where malaria is common. It is not known whether hydroxychloroquine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take hydroxychloroquine?

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

Take hydroxychloroquine with a meal or a glass of milk, unless your doctor tells you otherwise.

Hydroxychloroquine is sometimes given only once per week. Choose the same day each week to take this medication if you are on a weekly dosing schedule.

To prevent malaria: Start taking the medicine 2 weeks before entering an area where malaria is common. Continue taking the medicine regularly during your stay and for at least 8 weeks after you leave the area.

To treat malaria: Your doctor may recommend a single dose, or a high starting dose followed by a smaller dose 6 to 8 hours later for 2 days in a row. Follow your doctor's instructions.

Take this medicine for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated.

In addition to taking hydroxychloroquine, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could cause malaria.

Contact your doctor as soon as possible if you have been exposed to malaria, or if you have fever or other symptoms of illness during or after a stay in an area where malaria is common.

When treating lupus or arthritis, hydroxychloroquine is usually given daily for several weeks or months. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 6 months of treatment.

If you take hydroxychloroquine long-term, your doctor may need to check your knee and ankle reflexes and also do blood tests on a regular basis to check for harmful side effects. Your vision may also need to be tested every 3 months. Do not miss any scheduled appointments.

No medication is 100% effective in treating or preventing all types of malaria. For best results, keep using the medication as directed. Talk with your doctor if you have fever, vomiting, or diarrhea during your treatment.

Store at room temperature away from moisture, heat, and light.

See also: Hydroxychloroquine dosage (in more detail)

What happens if I miss a dose?

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

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of hydroxychloroquine can be fatal, especially in children.

Treatment of a hydroxychloroquine overdose must be started quickly. You may be told to induce vomiting right away (at home, before transport to an emergency room). Ask the poison control center how to induce vomiting in the case of a hydroxychloroquine overdose.

Overdose symptoms may include headache, drowsiness, vision changes, slow heart rate, chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, seizure (convulsions), shallow breathing, or breathing that stops.

What should I avoid while taking hydroxychloroquine?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Hydroxychloroquine side effects

Some people taking this medication over long periods of time or at high doses have developed irreversible damage to the retina of the eye. Stop taking hydroxychloroquine and call your doctor at once if you have trouble focusing, if you see light streaks or flashes in your vision, or if you notice any swelling or color changes in your eyes. 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 a serious side effect such as:

• 
  

  muscle weakness, twitching, or uncontrolled movement;

  
  


• 
  

  loss of balance or coordination;

  
  


• 
  

  blurred vision, light sensitivity, seeing halos around lights;

  
  


• 
  

  pale skin, easy bruising or bleeding;

  
  


• 
  

  confusion, unusual thoughts or behavior; or

  
  


• 
  

  seizure (convulsions).

  
  

Less serious side effects may include:

• 
  

  headache, ringing in your ears;

  
  


• 
  

  spinning sensation;

  
  


• 
  

  nausea, vomiting, stomach pain;

  
  


• 
  

  loss of appetite, weight loss;

  
  


• 
  

  mood changes, feeling nervous or irritable;

  
  


• 
  

  skin rash or itching; or

  
  


• 
  

  hair loss.

  
  

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

Hydroxychloroquine Dosing Information

Usual Adult Dose for Malaria:

Treatment of the acute attack: 800 mg (620 mg base) followed in 6 to 8 hours by 400 mg (310 mg base), then 400 mg (310 mg base) once a day for 2 consecutive days; alternatively, a single dose of 800 mg (620 mg base) has also been effective

Dosage on the basis of body weight:
First dose: 10 mg base/kg (not to exceed 620 mg base)
Second dose: 5 mg base/kg (not to exceed 310 mg base) 6 hours after first dose
Third dose: 5 mg base/kg 18 hours after second dose
Fourth dose: 5 mg base/kg 24 hours after third dose

Each dose should be taken with a meal or a glass of milk.

Concomitant therapy with an 8-aminoquinoline drug is necessary for the radical cure of vivax and malariae malaria.

Usual Adult Dose for Malaria Prophylaxis:

Suppression: 400 mg (310 mg base) orally on the same day every week

Suppressive therapy should begin 2 weeks prior to exposure; however, failing this, an initial dose of 800 mg (620 mg base) may be taken in 2 divided doses (6 hours apart). Suppressive therapy should continue for 8 weeks after leaving the endemic area.

Each dose should be taken with a meal or a glass of milk.

Usual Adult Dose for Rheumatoid Arthritis:

Initial dose: 400 to 600 mg (310 to 465 mg base) orally once a day
Maintenance dose: 200 to 400 mg (155 to 310 mg base) orally once a day

Each dose should be taken with a meal or a glass of milk.

Usual Adult Dose for Systemic Lupus Erythematosus:

Discoid and systemic lupus erythematosus:
Initial dose: 400 mg (310 mg base) orally once or twice a day for several weeks or months, depending on patient response
Maintenance dose: 200 to 400 mg (155 to 310 mg base) orally once a day

Each dose should be taken with a meal or a glass of milk.

Usual Pediatric Dose for Malaria:

Treatment of the acute attack:
1 year or older:
First dose: 10 mg base/kg (not to exceed 620 mg base)
Second dose: 5 mg base/kg (not to exceed 310 mg base) 6 hours after first dose
Third dose: 5 mg base/kg 18 hours after second dose
Fourth dose: 5 mg base/kg 24 hours after third dose

Each dose should be taken with a meal or a glass of milk.

Concomitant therapy with an 8-aminoquinoline drug is necessary for the radical cure of vivax and malariae malaria.

Usual Pediatric Dose for Malaria Prophylaxis:

Suppression:
1 year or older: 5 mg base/kg of body weight (not to exceed 310 mg base) orally on the same day every week

Suppressive therapy should begin 2 weeks prior to exposure; however, failing this, an initial dose of 10 mg base/kg (not to exceed 620 mg base) may be taken in 2 divided doses (6 hours apart). Suppressive therapy should continue for 8 weeks after leaving the endemic area.

Each dose should be taken with a meal or a glass of milk.

Usual Pediatric Dose for Dermatomyositis:

Case Review (n=25)
Juvenile Dermatomyositis (JDMS):
1.5 to 15 years: 7 mg/kg orally per day (added to first course treatment for JDMS if the patient presented with extensive skin rash and needed steroids in high doses)

Each dose should be taken with a meal or a glass of milk.

What other drugs will affect hydroxychloroquine?

Hydroxychloroquine can harm your liver. This effect is increased when you also use other medicines harmful to the liver. You may need dose adjustments or special tests if you have recently used:

• 
  

  acetaminophen (Tylenol);

  
  


• 
  

  cancer medications;

  
  


• 
  

  tuberculosis medications;

  
  


• 
  

  birth control pills or hormone replacement therapy;

  
  


• 
  

  arthritis medications such as auranofin (Ridaura) or methotrexate (Rheumatrex, Trexall);

  
  


• 
  

  an ACE inhibitor such as benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), ramipril (Altace), and others;

  
  


• 
  

  an antibiotic such as dapsone, erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), or rifampin (Rifater, Rifadin, Rifamate);

  
  


• 
  

  an antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), or ketoconazole (Nizoral);

  
  


• 
  

  cholesterol medications such as niacin (Advicor, Niaspan, Niacor, Simcor, Slo Niacin, and others), atorvastatin (Lipitor, Caduet), lovastatin (Mevacor, Altoprev, Advicor), simvastatin (Zocor, Simcor, Vytorin), and others;

  
  


• 
  

  HIV/AIDS medications such as lamivudine (Combivir, Epivir), abacavir/lamivudine/zidovudine (Trizivir), nevirapine (Viramune), tenofovir (Viread), or zidovudine (Retrovir);

  
  


• 
  

  an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or

  
  


• 
  

  seizure medications such as carbamazepine (Carbatrol, Tegretol), phenytoin (Dilantin), felbamate (Felbatol), valproic acid (Depakene).

  
  

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

More hydroxychloroquine resources

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

• hydroxychloroquine Advanced Consumer (Micromedex) - Includes Dosage Information


• Hydroxychloroquine MedFacts Consumer Leaflet (Wolters Kluwer)


• Hydroxychloroquine Sulfate Monograph (AHFS DI)

Compare hydroxychloroquine with other medications

• Dermatomyositis
• Lyme Disease, Arthritis
• Malaria
• Malaria Prevention
• Rheumatoid Arthritis
• Sjogren's Syndrome
• Systemic Lupus Erythematosus
• Undifferentiated Connective Tissue Disease

Where can I get more information?

• Your pharmacist can provide more information about hydroxychloroquine.

See also: hydroxychloroquine side effects (in more detail)

Sterile Talc

Prescribing Information

NDC 63256-200-05

Cat. # 1690

For Intrapleural Administration Only

Sterile Talc Description

Sterile Talc Powder is a sclerosing agent intended for intrapleural administration supplied in a single use 100 mL brown glass bottle, sealed with a gray, 20 mm stopper and covered with a flip-off seal. Each bottle contains a minimum of 5.0 g of Talc USP (Ultra 2000 Talc), either white or off-white to light gray, asbestos-free and brucite-free grade of talc of controlled particle size. The composition of the talc is ≥ 95% talc as hydrated magnesium silicate. The empirical formula of talc is Mg3 Si4 010 (OH)2 with a molecular weight of 379.3. Associated naturally occurring minerals include chlorite (hydrated aluminum and magnesium silicate.), dolomite (calcium and magnesium carbonate), calcite (calcium carbonate) and quartz. Talc is practically insoluble in water and in dilute solutions of acids and alkali hydroxides. The finished product has been sterilized by gamma irradiation.

Sterile Talc - Clinical Pharmacology

Mechanism of Action

The therapeutic action of talc instilled into the pleural cavity is believed to result from induction of an inflammatory reaction. This reaction promotes adherence of the visceral and parietal pleura, obliterating the pleural space and preventing reaccumulation of pleural fluid.

The extent of systemic absorption of talc after intrapleural administration has not been adequately studied. Systemic exposure could be affected by the integrity of the pleural surface, and therefore could be increased if talc is administered immediately following lung resection or biopsy.

Clinical Studies

The data demonstrating safety and efficacy of talc slurry administered via chest tube for the treatment of patients with malignant pleural effusions are from the published medical literature. The following prospective, randomized studies were designed to evaluate the risk of recurrence of malignant pleural effusions in patients with a variety of solid tumors. The studies compared talc slurry, instilled into the pleural cavity via chest tube, versus a concurrent control. In all studies, after maximal drainage of the pleural effusion, the investigator administered talc slurry via chest tube. Chest films documented response (defined as lack of recurrence of fluid for a period of time). Studies differed on the timing of the efficacy assessment. Zimmer et al. did not specify the time required evaluations. Ong et al. specified the assessment at one month. Sorensen et al. specified the assessment at 3-4 months. The remaining studies assessed response at the completion of the follow-up period.

Randomized Controlled Trials Using Talc Slurry as a Sclerosing Agent

*   Two-sided p-value based on Fisher's exact test
a   Patients were evaluable if chest x-rays were done to assess response per protocol.
The Sorensen study excluded patients if incomplete lung re-expansion was noted post drainage.
b   Data per procedure (33 procedures in 29 evaluable patients, 3 patients with bilateral effusions).
c   Plus lidocaine 1%, 20 mL.
d   Plus lidocaine 1%, 10 mL.
REFERENCE	TREATMENT	RESPONSE RATE EVALUABLE PTS* p value*	RESPONSE RATE ALL PTS* p value*
Sorensen et al. Eur J Respir Dis. 1984: 65(2):131-5	Talc Slurry 10g /250ml NS vs. Chest tube drainage alone	100% (9/9) vs. 58% (7/12) p=0.04	64% (9/14) vs. 41% (7/17) p=0.29
Noppen et al. Acta Clin Belg 1997; 52(4):258-62	Talc Slurry 5g/50-ml NS vs. Bleomycin 1mg/kg/50ml NS	79% (11/14) vs. 75% (9/12) p=1.00	79% (11/14) vs. 75% (9/12) p=1.00
Zimmer PW et al. Chest 1997; 112(2):430-434	Talc Slurry 5g/50 ml NSc vs. Bleomycin 60U/50 ml NSc	90% (17/19b) vs. 79% (11/14 b) p=0.63	Not Given
Ong KC et al. Respirology 2000; 5:99-103	Talc Slurry 5g/150ml NSd vs. Bleomycin 1U/kg/150 ml NSd	89% (16/18) vs. 70% (14/20) p=0.24	64% (16/25) vs. 56% (14/25) p=0.77
Yim AP et al. Ann Thorax Surg 1996; 62:1655-8	Talc Slurry 5g/50ml NS, lidocaine 2% 10 ml vs. Talc Insufflation 5g powder	90%(26/29) vs. 96% (27/28) p=0.61	90% (26/29) vs. 96% (27/28) p=0.61

In single-arm studies of malignant pleural effusions from the published literature, variously defined "success" rates using talc slurry pleurodesis ranged from 75% to 100%.

Indications and Usage for Sterile Talc

Sterile Talc Powder, administered intrapleurally via chest tube, is indicated as a sclerosing agent to decrease the recurrence of malignant pleural effusions in symptomatic patients.

Contraindications

None known

Warnings

None

Precautions

1.   Future procedures: The possibility of the future diagnostic and therapeutic procedures involving the hemithorax to be treated must be considered prior to administering Sterile Talc Powder. Sclerosis of the pleural space may preclude subsequent diagnostic procedures of the pleura on the treated side. Talc sclerosis may complicate or preclude future ipsilateral lung resective surgery, including pneumonectomy for transplantation purposes.

2.   Use in potentially curable disease: Talc has no known antineoplastic activity and should not be used alone for potentially curable malignancies where systemic therapy would be more appropriate, e.g., a malignant effusion secondary to a potentially curable lymphoma.

3.   Pulmonary complications: Acute Pneumonitis and Acute Respiratory Distress Syndrome (ARDS) have been reported in association with intrapleural talc administration. Three of the case reports of ARDS have occurred after treatment with a relatively large talc dose (10 g) administered via intrapleural chest tube instillation. One patient died one month post treatment and two patients recovered without further sequelae.

DRUG INTERACTIONS

It is not known whether the effectiveness of a second sclerosing agent after prior talc pleurodesis would be diminished by the absorptive properties of talc.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies on the carcinogenicity of talc have been performed using non-standard designs which prevent firm conclusions on its carcinogenicity. With single intraperitoneal administration to mice at 20 mg and observation for at least 6 months or 4 weekly doses administered intraperitoneally at 25 mg/dose to rats with observation for at least 84 weeks, tumor incidence was not increased. In these studies the talc and its asbestos content were not characterized.

Genotoxicity was tested in cultures of rat pleural mesothelial cells (RPMC) as unscheduled DNA synthesis (UDS) and sister chromatid exchanges (SCEs). None of the talc samples (which were asbestos-free) induced enhancement of UDS or SCEs in treated cultures. No information is available on impairment of fertility in animals by talc.

Pregnancy: Pregnancy Category B. An oral administration study has been performed in the rabbit at 900 mg/kg. Approximately 5 fold higher than a human dose on mg/m2 basis, and has revealed no evidence of teratogenicity due to talc. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the benefit outweighs the risk.

Pediatric Use: The safety and efficacy of Sterile Talc Powder in pediatric patients have not been established.

Geriatric use: The estimated mean and median ages of patients treated with talc slurry from clinical studies (single-arm or randomized) were 60 and 62 years, respectively. No analyses to specifically evaluate the safety and efficacy in the geriatric population have been reported.

Adverse Reactions

Intrathoracic administration of talc slurry has been described in medical literature reports involving more that 2000 patients. Patients with malignant pleural effusions were treated with talc via poudrage or slurry. In general, with respect to reported adverse experiences, it is difficult to distinguish the effects of talc from the effects of the procedure(s) associated with its administration. The most often reported adverse experiences to intrapleurally-administered talc were fever and pain.

Infection: Complications reported include empyema.

Respiratory: Complications reported include hypoxemia, dyspnea, unilateral pulmonary edema, pneumonia, ARDS, brochopleural fistula, hemoptysis and pulmonary emboli.

Cardiovascular: Complications reported included tachycardia, myocardial infarction, hypotension, hypovolemia and asystolic arrest

Delivery Procedure: Adverse reactions due to the delivery procedure and the chest tube may include: pain, infection at the site of thoracostomy or thoracoscopy, localized bleeding, and subcutaneous emphysema.

Chronic Toxicity: Since patients in clinical studies had a limited life expectancy, data on chronic toxicity are limited

Overdosage

No definite relationship between dose and toxicity has been established. Excessive talc may be partially removed with saline lavage.

Sterile Talc Dosage and Administration

Sterile Talc Powder should be administered after adequate drainage of the effusion. The success of the pleurodesis appears to be related to the completeness of the drainage of the pleural fluid, as well as the full re-expansion of the lung, both of which will promote symphysis of the pleural surfaces.

The recommended dose is 5 g, dissolved in 50 - 100 ml Sodium Chloride Injection, USP.  Although the optimal dose for effective pleurodesis is unknown, 5 g was the dose most frequently reported in the published literature.

Talc Preparation

Prepare the talc slurry using aseptic technique in an appropriate laminar flow hood. Remove talc container from packaging. Remove protective flip-off seal.

Each brown bottle contains 5 g of Sterilized Talc Powder. To dispense the contents:

1. Using a 16 gauge needle attached to a 60-mL LuerLok syringe, measure and draw up 50 mL of Sodium Chloride Injection, USP.  Vent the talc bottle using a needle. Slowing inject the 50 mL of Sodium Chloride Injection, USP  into the bottle. For doses more than 5 g, repeat this procedure with a second bottle.


2. Swirl the bottle(s) to disperse the talc powder and continue swirling to avoid settling of the talc in the slurry. Each bottle will contain 5 g Sterile Talc Powder dispersed in 50 mL of Sodium Chloride Injection, USP.


3. Divide the content of each bottle into two 60 mL irrigation syringes by withdrawing 25 mL of the slurry into each syringe with continuous swirling. QS each syringe with Sodium Chloride Injection, USP  to a total volume of 50 mL in each syringe. Draw air into each syringe to the 60 mL mark to serve as a headspace for mixing prior to administration.


4. When appropriately labeled, each syringe contains 2.5 g of Sterile Talc in 50 mL of Sodium Chloride Injection, USP  with an air headspace of 10 mL. Once the slurry has been made, use within 12 hours or discard and prepare fresh slurry. Label the syringes appropriately noting the expiration date and time, with the statement “For Pleurodesis Only – NOT FOR IV ADMINISTRATION,” the identity of the patient intended to receive this material and a cautionary statement to SHAKE WELL before use.


5. Prior to administration, completely and continuously agitate the syringes to evenly redisperse the talc and avoid settlement. Immediately prior to administration, vent the 10mL air headspace from each syringe.


6. Attach the adapter and place a syringe tip on the adapter. Maintain continuous agitation of the syringes.

NOTICE: Shake well before installation. Each 25 ml of prepared slurry in the syringe contains 1.25 g of talc. NOT FOR IV ADMINISTRATION.

Administration

Administer the talc slurry through the chest tube by gently applying pressure to syringe plunger and empty the contents of the syringe into the chest cavity. After application, discard the empty syringe according to general hospital procedures. After the talc slurry has been administered through the chest tube into the pleural cavity, the chest tube may be flushed with 10- 25 mL sodium chloride solution to ensure that the complete dose of talc is delivered.

Following introduction of the talc slurry, the chest drainage tube is clamped, and the patient is asked to move, at 20 to 30 minute intervals, from supine to alternating decubitus positions, so that over a period of about 2 hours the talc is distributed within the chest cavity. Recent evidence suggests that this step may not be necessary.

At the end of this period, the chest drainage tube is unclamped, and the excess saline is removed by the routine continual external suction on the tube.

How is Sterile Talc Supplied

NDC 63256-200-05 Sterile Talc Powder is supplied in a 100 mL brown glass bottle containing 5 g of talc. The sterile bottle is closed with a gray stopper and covered with a flip-off seal.

Storage: Store at Room Temperature (18-25°C). Protect against sunlight.

DISTRIBUTED BY: Bryan Corporation. Woburn, MA 01801

Version: Original Sep 2003

TALC  talc  aerosol, powder

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63256-200 Route of Administration INTRAPLEURAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Talc (Talc) Active 5 GRAM  In 1 CANISTER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63256-200-05 1 CANISTER In 1 CANISTER None

Revised: 10/2006Bryan Corporation

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