1 INDICATIONS & USAGE Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.

• Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.

(1) • Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.

(1) 1.1 HIV-1 Infection Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.

The following points should be considered when initiating therapy with tenofovir disoproxil fumarate tablets for the treatment of HIV-1 infection: • Tenofovir disoproxil fumarate tablets should not be used in combination with ATRIPLA ® , BIKTARVY ® , COMPLERA ® , DESCOVY ® , GENVOYA ® , ODEFSEY ® , STRIBILD ® , TRUVADA ® , or VEMLIDY ® [See Warnings and Precautions (5.4)].

1.2 Chronic Hepatitis B Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.

The following points should be considered when initiating therapy with tenofovir disoproxil fumarate tablets for the treatment of chronic hepatitis B infection: • The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine.

Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].

• Tenofovir disoproxil fumarate tablets were evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease [See Adverse Reactions (6.1), Clinical Studies (14.2)].

• The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy [See Microbiology (12.4), Clinical Studies ( 14.2)].

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions ( 5.1 )].

• New Onset or Worsening Renal Impairment [See Warnings and Precautions ( 5.2 )].

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions ( 5.3 )].

• Bone Effects [See Warnings and Precautions ( 5.6 )].

• Immune Reconstitution Syndrome [See Warnings and Precautions ( 5.7)].

• In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea.

(6.1) • In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%).

(6.1) • In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults.

(6.1) • In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (incidence greater than or equal to 10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Clinical Trials in Adult Patients with HIV-1 Infection More than 12,000 subjects have been treated with tenofovir disoproxil fumarate tablets alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs.

A total of 1,544 subjects have received tenofovir disoproxil fumarate tablets 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate tablets in expanded access programs.

The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Treatment-Naïve Patients Study 903 - Treatment-Emergent Adverse-Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received tenofovir disoproxil fumarate tablets (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) 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 treatment-emergent moderate to severe adverse reactions are summarized in Table 4.

Table 4 Selected Treatment-Emergent Adverse Reactionsa (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Study 903 (0 to 144 Weeks) Tenofovir disoproxil fumarate Tablets +3TC+EFV d4T+3TC+EFV N=299 N=301 Body as a Whole Headache Pain Fever Abdominal pain Back pain Asthenia 14% 13% 8% 7% 9% 6% 17% 12% 7% 12% 8% 7% Digestive System Diarrhea Nausea Dyspepsia Vomiting 11% 8% 4% 5% 13% 9% 5% 9% Metabolic Disorders Lipodystrophy b 1% 8% Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous System Depression Insomnia Dizziness Peripheral neuropathy c Anxiety 11% 5% 3% 1% 6% 10% 8% 6% 5% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event d 18% 12% a.

Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b.

Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.

c.

Peripheral neuropathy includes peripheral neuritis and neuropathy.

d.

Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir disoproxil fumarate tablets (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate tablets and stavudine treatment arms.

A summary of Grades 3 to 4 laboratory abnormalities is provided in Table 5.

Table 5 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Study 903 (0 to 144 Weeks) Tenofovir disoproxil fumarate Tablets+3TC+EFV d4T+3TC+EFV N=299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (>240 mg/dL) 19% 40% Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12% Serum Amylase (>175 U/L) 9% 8% AST (M: >180 U/L; F: >170 U/L) 5% 7% ALT (M: >215 U/L; F: >170 U/L) 4% 5% Hematuria (>100 RBC/HPF) 7% 7% Neutrophils (<750/mm 3 ) 3% 1% Fasting Triglycerides (>750 mg/dL) 1% 9% Study 934 – Treatment-Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either tenofovir disoproxil fumarate tablets + EMTRIVA ® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254).

Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6).

Changes in Bone Mineral Density 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 tenofovir disoproxil fumarate tablets + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1% ± 4.6) through 144 weeks.

Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir disoproxil fumarate tablets group vs.

-2.4% ± 4.5 in the stavudine group).

In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144.

Twenty-eight percent of tenofovir disoproxil fumarate tablets-treated subjects vs.

21% of the stavudine-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 tenofovir disoproxil fumarate tablets group and 6 subjects in the stavudine 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 tenofovir disoproxil fumarate tablets group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [See Warnings and Precautions (5.6)].

Table 6 Selected Treatment-Emergent Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Study 934 (0 to 144 Weeks) Tenofovir disoproxil fumarate Tablets b +FTC+EFV AZT/3TC+EFV N=257 N=254 Gastrointestinal Disorder Diarrhea Nausea Vomiting 9% 9% 2% 5% 7% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis Upper respiratory tract infections Nasopharyngitis 8% 8% 5% 4% 5% 3% Nervous System Disorders Headache Dizziness 6% 8% 5% 7% Psychiatric Disorders Depression Insomnia 9% 5% 7% 7% Skin and Subcutaneous Tissue Disorders Rash event c 7% 9% a.

Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b.

From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate tablets + EMTRIVA with efavirenz.

c.

Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).

Table 7 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0 to 144 Weeks) Tenofovir disoproxil fumarate a Tablets+FTC+EFV AZT/3TC+EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L; F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L; F: >170 U/L) 3% 3% ALT (M: >215 U/L; F: >170 U/L) 2% 3% Hemoglobin (<8 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (³3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a.

From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate tablets + EMTRIVA with efavirenz.

Treatment-Experienced Patients Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence.

Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).

A summary of moderate to severe treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8.

Table 8 Selected Treatment-Emergent Adverse Reactionsa (Grades 2 to 4) Reported in ≥3% in Any Treatment Group in Study 907 (0 to 48 Weeks) Tenofovir disoproxil fumarate Tablets ( N=3 68) (Week 0 -2 4) Placebo ( N=1 82) (Week 0 -2 4) Tenofovir disoproxil fumarate Tablets ( N=3 68) (Week 0 -4 8) Placebo C rosso ver to T enofovir disoproxil fumarate Tablets ( N=1 70) (Week 2 4 -4 8) Body as a Whole Asthenia Pain He ad a che Abdomi nal p ain Back pain Ch e st pain Fever 7% 7% 5% 4% 3% 3% 2% 6% 7% 5% 3% 3% 1% 2% 11% 12% 8% 7% 4% 3% 4% 1% 4% 2% 6% 2% 2% 2% Dig estive System Diarr hea Na u s ea Vomiting Anorexia Dys pe psia Flatule nce 11% 8% 4% 3% 3% 3% 10% 5% 1% 2% 2% 1% 16% 11% 7% 4% 4% 4% 11% 7% 5% 1% 2% 1% R espiratory Pneum onia 2% 0% 3% 2% Ner vous S ys tem De pr ess ion Insomn ia Perip heral neuropathy b Dizzi ness 4% 3% 3% 1% 3% 2% 3% 3% 8% 4% 5% 3% 4% 4% 2% 1% Skin and A ppend age R ash event c Sweating 5% 3% 4% 2% 7% 3% 1% 1% Musculoskeletal Myalgia 3% 3% 4% 1% Metabol ic Wei ght loss 2% 1% 4% 2% a.

Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b.

Peripheral neuropathy includes peripheral neuritis and neuropathy.

c.

Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate tablets and placebo-treated groups.

A summary of Grades 3 to 4 laboratory abnormalities is provided in Table 9.

Table 9 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate Tablets-Treated Subjects in Study 907 (0 to 48 Weeks) Tenofovir disoproxil fumarate Tablets ( N=3 68) (Week 0-2 4) Placebo ( N=1 82) (Week 0-2 4) Tenofovir disoproxil fumarate Tablets ( N=3 68) (Week 0-4 8) Placebo Cro sso ver to Tenofovir disoproxil fumarate (N=170) (Week 24-48) Any ≥ Gra de 3 Lab orat ory Abnor mality 25% 38% 35% 34% Triglyceri des (> 750 mg/ dL) 8% 13% 11% 9% Cr eatine Kin ase (M: >9 90 U/ L; F: >845 U/L) 7% 14% 12% 12% Serum Amyl a se (>1 75 U/ L) 6% 7% 7% 6% Glycosuria (≥ 3+) 3% 3% 3% 2% AST (M: >180 U/L; F: >170 U/L) 3% 3% 4% 5% ALT (M: >215 U/L; F: >170 U/L) 2% 2% 4% 5% Serum Gl u c o se (>2 50 U/ L) 2% 4% 3% 3% Neutrophi ls (<7 50/mm 3 ) 1% 1% 2% 1% Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with tenofovir disoproxil fumarate tablets (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks.

The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate tablets were consistent with those observed in clinical trials in adults.

Eighty-nine pediatric subjects (2 to less than 12 years of age) received tenofovir disoproxil fumarate tablets in Study 352 for a median exposure of 104 weeks.

Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy.

Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score [See Warnings and Precautions (5.6)].

Changes in Bone Mineral Density: Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes.

In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir disoproxil fumarate tablets compared to the placebo treatment group.

Six tenofovir disoproxil fumarate tablets-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48.

Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with tenofovir disoproxil fumarate tablets for 96 weeks.

In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the tenofovir disoproxil fumarate tablets and the d4T or AZT treatment groups.

Total body BMD gain was less in the tenofovir disoproxil fumarate tablets compared to the d4T or AZT treatment groups.

One tenofovir disoproxil fumarate-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48.

Changes from baseline in BMD Z scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil fumarate tablets for 96 weeks.

In both trials, skeletal growth (height) appeared to be unaffected [See Warnings and Precautions (5.6)].

Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with tenofovir disoproxil fumarate tablets during the 48-week double-blind period experienced nausea: 9% with tenofovir disoproxil fumarate tablets versus 2% with HEPSERA.

Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with tenofovir disoproxil fumarate tablets included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.

During the open-label phase of treatment with tenofovir disoproxil fumarate tablets (weeks 48 to 384) in Studies 0102 and 0103, 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline.

No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks.

Laboratory Abnormalities: A summary of Grades 3 to 4 laboratory abnormalities through Week 48 is provided in Table 10.

Grades 3 to 4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate tablets treatment for up to 384 weeks in these trials.

Table 10 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir disoproxil fumarate -Treated Subjects in Studies 0102 and 0103 (0 to 48 Weeks) Tenofovir disoproxil fumarate Tablets (N=426) HEPSERA (N=215) Any ≥ Grade 3 Laboratory Abnormality 19% 13% Creatine Kinase (M: >990 U/L; F: >845 U/L) 2% 3% Serum Amylase (>175 U/L) 4% 1% Glycosuria (≥3+) 3% <1% AST (M: >180 U/L; F: >170 U/L) 4% 4% ALT (M: >215 U/L; F: >170 U/L) 10% 6% The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between tenofovir disoproxil fumarate tablets (2.6%) and HEPSERA (2%).

ALT flares generally occurred within the first 4 to 8 weeks of treatment and were accompanied by decreases in HBV DNA levels.

No subject had evidence of decompensation.

ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with tenofovir disoproxil fumarate tablets were consistent with those observed in other hepatitis B clinical trials in adults.

Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with tenofovir disoproxil fumarate tablets or other antiviral drugs for up to 48 weeks [See Clinical Studies (14.2)].

Among the 45 subjects receiving tenofovir disoproxil fumarate tablets, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%).

Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease.

Three of 45 (7%) subjects discontinued treatment due to an adverse event.

Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48).

Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure.

Because both tenofovir disoproxil fumarate tablets and decompensated liver disease may have an impact on renal function, the contribution of tenofovir disoproxil fumarate tablets to renal impairment in this population is difficult to ascertain.

One of 45 subjects experienced an on-treatment hepatic flare during the 48-Week trial.

Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with tenofovir disoproxil fumarate tablets (N=52) or placebo (N=54) for 72 weeks.

The adverse reactions observed in pediatric subjects who received treatment with tenofovir disoproxil fumarate tablets were consistent with those observed in clinical trials of tenofovir disoproxil fumarate tablets in adults.

In this study, both the tenofovir disoproxil fumarate tablets and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population.

The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in tenofovir disoproxil fumarate-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively).

Three subjects in the tenofovir disoproxil fumarate tablets group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72.

At baseline, mean BMD Z-scores in subjects randomized to tenofovir disoproxil fumarate tablets were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body.

In subjects receiving tenofovir disoproxil fumarate tablets for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo.

As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected [See Warnings and Precautions ( 5.6)].

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tenofovir disoproxil fumarate tablets.

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 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 Renal and Urinary Disorders 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 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.