Combivir

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with zidovudine. You will find a full list in the manufacturer's information leaflet supplied with your medicine. You should, however, speak with your doctor if you develop any of the following side-effects. This is because some of the common side-effects of zidovudine are similar to the symptoms of lactic acidosis - a less common but more serious problem.

Your doctor will discuss with you the possibility of lactic acidosis occurring. Let your doctor know straightaway if you develop any of the following symptoms:

• Feeling or being sick, tummy pain, loss of appetite, loss of weight, feeling weak or dizzy, and fast or gasping breathing.

If you experience any other symptoms which you think may be due to the medicine, speak with your doctor or pharmacist for further advice.

Combivir is part of the drug class:

• Nucleoside and nucleotide reverse transcriptase inhibitors

Consult your doctor at your next visit if any of the following undesirable events occur:

• signs of an allergic reaction such as rash, hives, itching, swelling, and difficulty breathing or swallowing
• signs of lactic acidosis such as muscle or stomach pain, extreme weakness or tiredness, feeling cold, enlarged or tender liver, and weight loss
• and frequent infections

Commonly reported side effects include:

• nausea and vomiting
• headaches
• fatigue
• diarrhea
• a general feeling of being unwell

Tell your healthcare provider about any side effect that is bothersome or does not go away.

This is not a complete list of this medication's side effects. Ask your doctor or pharmacist for more information.

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

Before receiving Combivir, talk to your doctor or pharmacist if you:

• ever had to stop taking this or another medication for this illness because you were allergic to them or they caused problems.
• had, or you have, any diseases of the kidney.
• had, or you have, any diseases of the liver, particularly hepatitis B infection.
• had, or you have, very low red blood cell count (severe anemia) or very low white blood cell count (neutropenia).
• are taking ribavarin as it could cause or worsen anemia (symptoms of tiredness, shortness of breath). Your doctor will advise whether you should stop taking this medication.
• are pregnant or breastfeeding.

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

Combivir comes as a tablet to be taken by mouth, usually twice daily. It can be taken with or without food.

If you forget to take your medicine, take it as soon as you remember. Then continue as before.

Do not double dose to make up for a forgotten dose.

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B

Zidovudine, one of the 2 active ingredients in this medication, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease.

Prolonged use of zidovudine has been associated with symptomatic myopathy.

Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of this medication. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue this medication and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Combivir, a combination of 2 nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.

Combivir is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.

Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:

Do not take Combivir if you have ever had an allergic reaction to any medicine that contains lamivudine or zidovudine.

Zidovudine can weaken your immune system and cause signs of infection (fever, mouth sores, skin sores, flu symptoms, pale skin). Your blood will need to be tested often. Long-term use of zidovudine can cause muscle weakness, or loss of muscle tissue similar to "wasting syndrome" caused by HIV.

Combivir may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

If you have hepatitis B you may develop liver symptoms after you stop taking medicine that contains lamivudine. Your doctor may want to check your liver function for several months after you stop using Combivir.

Do not take Combivir if you have ever had an allergic reaction to any medicine that contains lamivudine, zidovudine, or emtricitabine. This includes Atripla, Complera, Emtriva, Epivir, Epzicom, Retrovir, Stribild, Trizivir, and Truvada.

Some people develop a life-threatening condition called lactic acidosis while taking Combivir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.

Combivir can also cause severe or fatal liver problems. Tell your doctor if you have liver disease, especially hepatitis B.

Do not take Combivir with any other medicine that contains lamivudine, zidovudine, or emtricitabine. This includes Atripla, Combivir, Complera, Emtriva, Epivir, Epzicom, Retrovir, Stribild, Trizivir, and Truvada.

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

• kidney disease;

• pancreas disorder (especially in a child taking this medicine); or

• if you take ribavirin to treat hepatitis C.

It is not known whether Combivir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of Combivir on the baby.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Combivir should not be used to treat HIV in adolescents weighing less than 66 pounds.

Breastfeeding is not recommended during use of this drug. If replacement feeding is not an option, the WHO recommends a triple-drug regimen for HIV-infected women who are nursing; both drugs are included in alternative regimens. Excreted into human milk: Yes Comments: -The effects in the nursing infant are unknown; risk of neutropenia and severe anemia may increase with zidovudine-containing regimens. -The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. -Local guidelines should be consulted if replacement feeding is not an option.

LAMIVUDINE: Based on more than 200 mother/child pairs treated for HIV, serum lamivudine levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age. Milk samples were obtained daily before breastfeeding. The milk lamivudine level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L) with 300 mg twice a day (n=10) and 0.9 mg/L (range: less than 0.5 to 8.2 mg/L) with 150 mg twice a day plus zidovudine (n=10). Milk samples from 20 women taking lamivudine 150 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were obtained at 2 or 5 months postpartum, about 4 hours (range: 1 to 8.5 hours) after the last dose. The drug level in breast milk averaged 1.8 mg/L and the infant serum lamivudine level averaged 28 mcg/L (range: less than 14 to 53 mcg/L). Breast milk from 15 women and blood samples from 24 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using lamivudine 150 mg twice a day for 53 to 182 days (with [abacavir or lopinavir-ritonavir] and zidovudine). Breast milk was obtained right before a dose; whole breast milk lamivudine levels averaged 0.14 mg/L (about 74% of maternal blood levels). Infant blood was obtained 11 to 18 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Plasma lamivudine levels were undetectable (less than 7 mcg/L) in all infant samples. Serum and breast milk from 58 mothers using lamivudine 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started lamivudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk lamivudine level averaged 1214 mcg/L (all visits). The infant dried blood spot lamivudine levels averaged 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14, and were not measurable (less than 16 mcg/L) at week 24 postpartum. A fully breastfed infant would receive 182 mcg/kg/day of lamivudine (estimated). Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and [zidovudine or stavudine]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk lamivudine levels averaged 0.4 mg/L (n=20) for the first sample and 0.4 mg/L (n=30) for the second sample; these levels were 2.9 to 3.3 times the coinciding maternal serum levels. Mothers using lamivudine (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk lamivudine levels at about 14 hours after the last dose averaged 510 (17 samples), 387 (17 samples), and 310 mcg/L (13 samples). Milk levels were about 2.6 times (interquartile range: 1.1 to 3.5 times) the maternal plasma levels; milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum levels measured about 14 hours after the last maternal dose averaged 13, 10, and 5 mcg/L at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age, respectively, which was 6% of the maternal serum level. A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using lamivudine 150 mg twice a day as part of cART and 64 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. Breast milk lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). Infant plasma lamivudine level averaged 18 mcg/L (range: 7 to 35 mcg/L), which averaged 2% (range: 0 to 4%) of the maternal serum level. In a continuation of this study, 65 breast milk samples (after the same dose at 1, 3, and 6 months postpartum) and 22 blood samples (from 17 breastfed infants [extent not provided] between 1 and 6 months) were collected for drug analysis; lamivudine levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Unclear if some of the same patients from the first study were in the latter study. Mothers (n=30) starting lamivudine 150 mg orally twice a day (with zidovudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 at each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable lamivudine levels (at least 10 mcg/L) were found in 107 of 121 breast milk samples and 107 of 115 infant plasma samples; breast milk level averaged 0.94 mg/L over the 6 hours and infant plasma level averaged 180 mcg/L. ZIDOVUDINE: After administration of a single 200 mg dose to 13 HIV-infected women, the mean zidovudine concentration was similar in human milk and serum. Milk samples were collected 1, 2, 4, and 6 hours after a single 200 mg oral dose in 6 women. Peak milk zidovudine level averaged 857 mcg/L (range: 472 to 1043 mcg/L) at 1 to 2 hours postdose in 4 women and an hour later in the others. At either 2 or 5 months postpartum, milk from 18 women using zidovudine 300 mg orally twice a day (as part of cART) and serum levels from their infants were analyzed; the infants were also receiving zidovudine 4 or 6 mg/kg orally 3 times a day (depending on age). Milk and serum samples were collected about 4 hours (range: 1 to 8.5 hours) after the last dose. Zidovudine level averaged 207 mcg/L in breast milk and 123 mcg/L (range: 14 to 3302 mcg/L) in infant serum. Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and zidovudine [or stavudine if hemoglobin less than 8 g/dL]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk zidovudine levels averaged 130 mcg/L (n=11) for the first sample and 150 mcg/L (n=13) for the second sample; these levels were equal to the coinciding maternal serum levels. Serum and breast milk from 58 mothers using zidovudine 200 mg twice a day (with lamivudine and nevirapine) and serum levels from their 58 infants were analyzed. Mothers started zidovudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk zidovudine level averaged 9 mcg/L (35 selected samples [from all visits]). The infant dried blood spot zidovudine level averaged 24 mcg/L at delivery (16 selected samples; 8 had quantifiable levels); zidovudine levels from 66 samples collected at 2, 6, 14, and 24 weeks postpartum were not measurable (less than 30 mcg/L). A total of 114 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 38 mothers using zidovudine 300 mg twice a day as part of cART and 34 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. Breast milk zidovudine level averaged 33 mcg/L (range: 5 to 117 mcg/L). Infant plasma zidovudine levels ranged from 0 to 2.5 mcg/L, which averaged 2% (range: 0 to 5%) of the maternal serum level. Breast milk samples from 15 women were collected about 1 month postpartum and blood samples from their partially or exclusively breastfed infants were collected about 1 month (n=24) and 3 months (n=9) postpartum; the mothers were using zidovudine 300 mg twice a day for 53 to 182 days (as part of cART). Breast milk was obtained right before a dose; whole breast milk zidovudine levels averaged 7 mcg/L. Infant blood was obtained at various times after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Serum zidovudine levels were undetectable (less than 45 mcg/L) in all infant samples. Mothers (n=30) starting zidovudine 300 mg orally twice a day (with lamivudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 at each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable zidovudine levels (at least 10 mcg/L) were found in 98 of 121 breast milk samples and 0 of 115 infant plasma samples; breast milk level averaged 0.2 mg/L over the 6 hours. In a study to prevent maternal-to-child transmission of HIV infection, pregnant women used zidovudine alone or highly-active antiretroviral therapy (HAART: zidovudine, lamivudine, and nevirapine). After delivery, all infants (some breastfed; others formula fed) received 1 month of zidovudine prophylaxis. At 1 month of age, 15.9% of infants exposed to HAART had neutropenia compared to 3.7% of those not exposed. Hematologic toxicity was transient and asymptomatic. No differences in hematologic toxicity (from 2 to 6 months postpartum) and no statistical difference in hepatic toxicity were observed between the breastfed and formula-fed infants. In another study for prevention of maternal-to-child transmission of HIV infection, rates of severe anemia were compared in 3 groups of infants who received zidovudine prophylaxis. Through 6 months of age, severe anemia was observed in 7.4% of breastfed infants whose mothers received HAART, 5.3% of breastfed infants whose mothers received only zidovudine, and 2.5% of formula-fed infants. In general, the anemia responded well to iron and multivitamin supplementation and zidovudine discontinuation.