Cimduo

CIMDUO™ (lamivudine and tenofovir disoproxil fumarate) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg.

Dosage Forms And Strengths

Tablets: 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

The tablets are white to off-white, film-coated, oval tablets debossed with “M112” on one side and plain on the other side.

Storage And Handling

CIMDUO (lamivudine and tenofovir disoproxil fumarate) tablets 300 mg/300 mg are white to off-white, film-coated, oval tablets debossed with “M112” on one side and plain on the other side.

They are supplied as follows:

NDC 49502-450-93 cartons containing bottles of 30 tablets with desiccant, induction seal and child-resistant cap

NDC 49502-450-77 cartons containing bottles of 90 tablets with desiccant, induction seal and child-resistant cap

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature.]

Dispense in original container.

Manufactured for: Mylan Specialty L.P., Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited, Hyderabad — 500 096, India. Revised: Feb 2018

The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [see WARNINGS AND PRECAUTIONS].
• Exacerbations of Hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• New Onset or Worsening Renal Impairment [see WARNINGS AND PRECAUTIONS].
• Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS].
• Pancreatitis [see WARNINGS AND PRECAUTIONS].
• Decreases in Bone Mineral Density [see WARNINGS AND PRECAUTIONS].
• Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS].
• Fat Redistribution [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

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

Lamivudine And Tenofovir Disoproxil Fumarate

Study 903 -Adverse Reactions

The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naive subjects received TDF (N = 299) or stavudine (d4T) (N = 301) in combination with 3TC and EFV for 144 weeks were mild to moderate gastrointestinal events and dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected moderate to severe adverse reactions are summarized in Table 1.

Table 1: Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks)

With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 2.

Table 2: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Tenofovir Disoproxil Fumarate Treated Subjects in Study 903 (0-144 Weeks)

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see WARNINGS AND PRECAUTIONS].

In HIV-1-infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use for each of the individual components of CIMDUO (3TC and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to 3TC and TDF.

Body as a Whole: redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS].

Endocrine and Metabolic: hyperglycemia.

General: weakness.

Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Hypersensitivity: anaphylaxis, urticaria.

Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus.

Immune System Disorders: allergic reaction, including angioedema.

Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.

Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.

Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.

Renal and Urinary Disorders: renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria [see WARNINGS AND PRECAUTIONS].

Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).

Skin and Subcutaneous Tissue Disorders: rash.

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.

General Disorders and Administration Site Conditions: asthenia.

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Lamivudine

There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

Tenofovir Disoproxil Fumarate

Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

You should not take Cimduo if you:

• are allergic to lamivudine, tenofovir disoproxil fumarate, or any of the other ingredients. See the end of this Patient Information leaflet for a complete list of ingredients.

Applies to lamivudine/tenofovir: oral tablet

General

In a controlled trial with lamivudine, tenofovir disoproxil fumarate (DF), and efavirenz, the most common side effects were mild-to-moderate gastrointestinal events and dizziness. Mild side effects (grade 1) were common and included dizziness, diarrhea, and nausea.[Ref]

Metabolic

Very common (10% or more): Elevated fasting cholesterol (19%)
Uncommon (0.1% to 1%): Lipodystrophy, elevated fasting triglycerides
Frequency not reported: Higher 1,25 vitamin D levels

Lamivudine:
-Postmarketing reports: Hyperglycemia, lactic acidosis, redistribution/accumulation of body fat

Tenofovir DF:
-Postmarketing reports: Lactic acidosis, hypokalemia, hypophosphatemia

Combination antiretroviral therapy:
-Frequency not reported: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")[Ref]

Elevated fasting cholesterol (greater than 240 mg/dL) and fasting triglycerides (greater than 750 mg/dL) have been reported in 19% and 1% of patients using lamivudine, tenofovir DF, and efavirenz, respectively.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Hypokalemia and hypophosphatemia may occur as a result of proximal renal tubulopathy.[Ref]

Dermatologic

Very common (10% or more): Rash event (included rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash; 18%)

Lamivudine:
-Postmarketing reports: Urticaria, alopecia, pruritus

Tenofovir DF:
-Postmarketing reports: Rash[Ref]

Nervous system

Very common (10% or more): Headache (14%)
Common (1% to 10%): Dizziness
Uncommon (0.1% to 1%): Peripheral neuropathy (included peripheral neuritis, neuropathy)[Ref]

Other

Very common (10% or more): Pain (13%)
Common (1% to 10%): Fever, asthenia

Lamivudine:
-Postmarketing reports: Weakness

Tenofovir DF:
-Postmarketing reports: Asthenia[Ref]

Musculoskeletal

Very common (10% or more): Elevated creatine phosphokinase (12%)
Common (1% to 10%): Back pain, arthralgia, myalgia
Frequency not reported: Decreased bone mineral density, increased biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, urinary N telopeptide), clinically relevant fractures (excluding fingers and toes)

Lamivudine:
-Postmarketing reports: Muscle weakness, elevated creatine phosphokinase, rhabdomyolysis

Tenofovir DF:
-Postmarketing reports: Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy[Ref]

Elevated creatine phosphokinase (males: greater than 990 units/L; females: greater than 845 units/L) has been reported in 12% of patients using lamivudine, tenofovir DF, and efavirenz.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy may occur as a result of proximal renal tubulopathy.[Ref]

Gastrointestinal

Increased serum amylase (greater than 175 units/L) has been reported in 9% of patients using lamivudine, tenofovir DF, and efavirenz.

Pancreatitis (some cases fatal) has been reported in antiretroviral nucleoside-experienced pediatric patients using lamivudine alone or in combination with other antiretroviral agents.[Ref]

Very common (10% or more): Diarrhea (11%)
Common (1% to 10%): Nausea, increased serum amylase, abdominal pain, vomiting, dyspepsia

Lamivudine:
-Frequency not reported: Pancreatitis

Tenofovir DF:
-Postmarketing reports: Pancreatitis, increased amylase, abdominal pain[Ref]

Psychiatric

Very common (10% or more): Depression (11%)
Common (1% to 10%): Anxiety, insomnia[Ref]

Genitourinary

Common (1% to 10%): Hematuria

Tenofovir DF:
-Postmarketing reports: Proteinuria, polyuria[Ref]

Hematuria (greater than 100 RBC/high power field) has been reported in 7% of patients using lamivudine, tenofovir DF, and efavirenz.[Ref]

Hepatic

Common (1% to 10%): Elevated AST, elevated ALT

Lamivudine:
-Postmarketing reports: Hepatic steatosis, posttreatment exacerbation of hepatitis B

Tenofovir DF:
-Postmarketing reports: Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, GGT)

Combination antiretroviral therapy:
-Frequency not reported: Hepatic decompensation[Ref]

Elevated AST (males: greater than 180 units/L; females: greater than 170 units/L) and ALT (males: greater than 215 units/L; females: greater than 170 units/L) have been reported in 5% and 4% patients using lamivudine, tenofovir DF, and efavirenz, respectively.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and hepatitis B virus after discontinuation of lamivudine or tenofovir DF.

Hepatic decompensation (some fatal) has been reported in patients coinfected with HIV-1 and hepatitis C receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.[Ref]

Hematologic

Decreased neutrophils (less than 750/mm3) has been reported in 3% of patients using lamivudine, tenofovir DF, and efavirenz.[Ref]

Common (1% to 10%): Decreased neutrophils

Lamivudine:
-Postmarketing reports: Anemia (including pure red cell aplasia and severe anemias progressing on therapy)[Ref]

Respiratory

Common (1% to 10%): Pneumonia

Tenofovir DF:
-Postmarketing reports: Dyspnea[Ref]

Renal

Tenofovir DF:
-Postmarketing reports: Renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, increased creatinine[Ref]

Hypersensitivity

Lamivudine:
-Postmarketing reports: Anaphylaxis

Tenofovir DF:
-Postmarketing reports: Allergic reaction (including angioedema)[Ref]

Immunologic

Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

Endocrine

Frequency not reported: Higher serum parathyroid hormone levels[Ref]

Testing Prior to Initiation and During Treatment with Cimduo

Prior to initiation of Cimduo, test patients for hepatitis B virus infection [see Warnings and Precautions (5.2)].

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating Cimduo and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.3)].

Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg

Cimduo is a two-drug fixed-dose combination product containing 300 mg of lamivudine (3TC) and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of Cimduo in HIV-1-infected adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food.

Not Recommended in Renal Impairment

Because Cimduo is a fixed-dose combination tablet and cannot be dose adjusted, it is not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6)].

Clinical Efficacy in Patients with HIV-1 Infection

Trial 903

Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing EFV 600 mg + 3TC 300 mg + TDF 300 mg vs. EFV 600 mg + 3TC 300 mg + stavudine (d4T) 40 mg in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18-64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3-956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads > 100,000 copies/mL and 39% had CD4+ cell counts < 200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 7.

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤ 100,000 copies/mL) and CD4+ cell count (< or ≥ 200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the TDF and stavudine arms, respectively, achieved and maintained confirmed HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the TDF arm and 283 cells/mm3 for the stavudine arm.

Through 144 weeks, 11 subjects in the TDF group and 9 subjects in the stavudine group experienced a new CDC Class C event.

Lamivudine and tenofovir combination is used together with other antiviral medicines to treat human immunodeficiency virus (HIV) infection. HIV is the virus that causes acquired immune deficiency syndrome (AIDS).

This medicine does not cure or prevent HIV or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay the development of problems that usually result from AIDS or HIV disease. It will not keep you from spreading HIV to other people. People who receive this medicine may continue to have some of the problems usually related to AIDS or HIV disease.

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

Avoid taking other medications that contain an ingredient called sorbitol, often used as a sweetener in liquid medicines. Ask your pharmacist if you are not sure a medicine contains this ingredient.

Using this medicine will not prevent your disease from spreading. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Lamivudine and tenofovir can harm your kidneys, especially if you also use certain medicines for infections, cancer, osteoporosis, organ transplant rejection, bowel disorders, or pain or arthritis (including aspirin, Tylenol, Advil, and Aleve).

Other drugs may affect lamivudine and tenofovir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.